Arylsulfonamide-based matrix metalloprotease inhibitors

ABSTRACT

The present invention provides a compound of formula (I): 
     
       
         
         
             
             
         
       
     
     said compound is inhibitor of MMP-2, and/or MMP-8, and/or MMP-9, and/or MMP-12 and/or MMP-13, and thus can be employed for the treatment of a disorder or disease characterized by abnormal activity of MMP-2, and/or MMP-8, and/or MMP-9, and/or MMP-12 and/or MMP-13. Accordingly, the compound of formula (I) can be used in treatment of disorders or diseases mediated by MMP-2, and/or MMP-8, and/or MMP-9, and/or MMP-12, and/or MMP-13. Finally, the present invention also provides a pharmaceutical composition.

The present invention relates to novel compounds that are useful asinhibitors of matrix metalloproteinases such as matrix metalloproteinase2 (MMP-2), matrix metalloproteinase 8 (MMP-8), matrix metalloproteinase9 (MMP-9), matrix metalloproteinase 12 (MMP-12) and matrixmetalloproteinase 13 (MMP-13).

Matrix metalloproteinases (MMPs) are proteinases that are involved inthe breakdown and remodeling of the extracellular matrices (ECM) under avariety of physiological and pathological conditions. MMPs, whichcomprise a family of more than 20 members, use Zn²⁺ in the active sitesto catalyze hydrolyses of ECM. Based on their substrate specificities,they can be broadly classified into three subfamilies: collagenase,stromelysins and gelatinases.

Under normal physiological conditions, these enzymes serve manyimportant functions, including wound healing and tissue remodeling.However, when these enzymes are over activated, they can over-degradeECM, resulting in disease conditions. For example, MMP-2 and MMP-9 (bothare gelatinases) are thought to be involved in the pathogenesis ofinflammatory, infectious, and neoplastic diseases in many organs. Excessactivity of MMP-8, also known as collagenase-2 or neutrophilcollagenase, is associated with diseases such as pulmonary emphysema andosteoarthritis. See Balbin et al., “Collagenase 2 (MMP-8) expression inmurine tissue-remodeling processes, analysis of its potential role inpostpartum involution of the uterus,” J. Biol. Chem., 273(37):23959-23968 (1998). Excess activity of MMP-12, also known as macrophageelastase or metalloelastase, plays a key role in tumor invasion,arthritis, atherosclerosis, Alport syndrome, and chronic obstructivepulmonary disease (COPD). MMP-1 and MMP-13 are involved in theproteolysis of collagen. Excessive degradation of collagen is associatedwith the development of various diseases, including osteoarthritis. Seee.g., P. G. Mitchell et al., “Cloning, expression, and type IIcollagenolytic activity of matrix metalloproteinase-13 from humanosteoarthritic cartilage,” J Clin Invest. 1996 Feb. 1; 97(3): 761-768.

Many MMP inhibitors are known in the art. However, existing MMPinhibitors are typically based on hydroxamic acid derivatives. Forexample, U.S. Pat. No. 6,500,983 issued to Kottirsch et al. disclosesthe use of hydroxamic acid derivatives as MMP inhibitors. U.S. Pat. Nos.6,277,987 and 6,410,580 issued to Kukkola et al. disclose suflonyl aminoacid and sulfonylamino hydroxamic acid derivatives as MMP inhibitors.The hydroxamic acid moiety in these inhibitors binds to the active siteZn²⁺ to inhibit enzymatic activities.

While prior art hyroxamic acid-based MMP inhibitors are effective ininhibiting MMPs, there remains a need for different types of MMPinhibitors.

The present invention provides new MMP inhibitors that are based onarylsulfonamides. Various embodiments of the invention are describedherein. It will be recognised that features specified in each embodimentmay be combined with other specified features to provide furtherembodiments.

In one aspect, the present invention provides a compound of formula (I)

wherein

R₁ is selected from aryl, heteroaryl, heterocycloalkyl, each optionallysubstituted by one to five substitutents selected from the groupconsisting of 1) alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl,alkoxy, alkoxy-alkyl-, alkoxycarbonyl, R₄—O—, R₅C(O)—, R₆SO₂—,(R₇)NH—C(O)—, or (R₈)(R₉)N—, each of which is further optionallysubstituted by one to two substituents selected from halo, alkoxy,alkyl, hydroxy, dialkylamino, alkylsulfonyl, heterocycloalkyl, oraryloxy; or 2) hydroxy, halo, nitro, amino, carboxy, or HC(O)—;

R₂ and R₃ are independently hydrogen, or (C₁-C₇) alkyl.

R₄, R₅, R₆, R₇, R₈ and R₉ are independently alkyl, aryl, aryl-alkyl-,heterocycloalkyl, or heteroaryl each of which is further optionallysubstituted by one to five substituents selected from the groupconsisting of (C₁-C₇) alkyl, halo, hydroxy, (C₁-C₇) alkoxy, and aryl;and

X is selected from hydrogen, amine, cyano, halogen, nitro, alkyl-S—,alkyl-SO—, alkyl-SO₂—, H₂N—SO₂—, R₅—C(O)—, alkyl, or R₄—O, wherein R₄and R₅ are defined above; or

a pharmaceutically acceptable salt thereof, or an optical isomerthereof; or a mixture of optical isomers.

Preferably, the present invention provides compound formula (I), whereinR₁ is selected from (C₆-C₁₂) aryl, (5-14) membered heteroaryl, or (4-14)membered heterocycloalkyl, each of which is optionally substituted byone to three substituents selected from the group consisting of HC(O)—,(5-9) membered heteroaryl, or (4-9) membered heterocycloalkyl, (C₁-C₇)alkyl, (C₃-C₇) cycloakyl, R₄—O—, R₅—C(O)—, R₆—SO₂—, (R₇)NH—C(O)—, or(R₈)(R₉)N—, wherein R₄, R₅, R₆, R₇, R₅ and R₉ are independently (C₁-C₇)alkyl or (C₆-C₁₂) aryl, each of which is further optionally substitutedby one to two substituents selected from the group consisting of (C₁-C₇)alkyl, halo, hydroxy, (C₁-C₇) alkoxy, (C₆-C₁₂) aryl, (C₁-C₇)dialkylamino, or (4-9) membered heterocycloalkyl; R₂ and R₃ areindependently hydrogen, or (C₁-C₇) alkyl; X is selected from hydrogen,amine, cyano, halogen, nitro, alkyl-S—, alkyl-SO—, alkyl-SO₂—, H₂N—SO₂—,R₄—C(O)—, alkyl, or R₅—O—, wherein R₄ and R₅ are defined above; or

a pharmaceutically acceptable salt thereof, or an optical isomerthereof; or a mixture of optical isomers.

In one aspect, the present invention provides a compound of formula (II)

wherein R′₁ is selected from hydrogen, alkyl, alkoxy, cycloakyl, R₄—O—,R₅C(O)—, R₆SO₂—, (R₇)NH—C(O)—, or (R₈)(R₉)N—, aryl, heteroaryl,heterocycloalkyl, said aryl, heteroaryl, and heterocycloalkyl areoptionally substituted by one or two substituents selected fromhydroxyl, halo, alkyl, carboxyl, alkoxycarbonyl, and HC(O)—;

wherein R₄, R₅, R₆, R₇, R₈ and R₉ are independently alkyl or aryl eachof which is optionally substituted by one to five substituents selectedfrom the group consisting of (C₁-C₇) alkyl, halo, hydroxyl, (C₁-C₇)alkoxy, and aryl;

R₂ and R₃ are independently hydrogen, or (C₁-C₇) alkyl;

X is selected from hydrogen, cyano, halogen, nitro, alkyl-S—, alkyl-SO—,alkyl-SO₂—, H₂N—SO₂—, R₅—C(O)—, alkyl, or R₄—O, wherein R₄ and R₅ areindependently alkyl or aryl each of which is optionally substituted bysubstituents selected from the group consisting of (C₁-C₇) alkyl, halo,hydroxyl, (C₁-C₇) alkoxy, and aryl; or

a pharmaceutically acceptable salt thereof, or an optical isomerthereof; or a mixture of optical isomers.

Preferably, the present invention provides the compound of formula (II),wherein R′₁ is selected from (C₁-C₇) alkyl, (C₃-C₇) cycloalkyl, (C₁-C₇)alkoxy, HC(O)—, (5-9) membered heteroaryl, or (4-9) memberedheterocycloalkyl, or (C₆-C₁₂) aryl, said (C₆-C₁₂) aryl, (5-9) memberedheteroaryl, and (4-9) membered heterocycloalkyl are optionallysubstituted by one or two substituents selected from hydroxy, halo,(C₁-C₇) alkyl, carboxyl, (C₁-C₇) alkoxycarbonyl, and HC(O)—;

R₂ and R₃ are hydrogen;

X is halogen, or (C₁-C₇) alkoxy; or

a pharmaceutically acceptable salt thereof, or an optical isomerthereof; or a mixture of optical isomers.

In one aspect, the present invention provides a compound of formula(III)

wherein R′₁ is selected from hydrogen, alkyl, cycloakyl, R₅C(O)—,R₆SO₂—, (R₇)NH—C(O)—, or (R₅)(R₉)N—, aryl, heteroaryl, heterocycloalkyl,said aryl, heteroaryl, and heterocycloalkyl are optionally substitutedby one or two substituents selected from alkyl-SO₂—, alkyl-C(O)—,heterocycloalkyl-alkyl-, alkyl-alkoxy-, alkoxy-, alkyl, aryl,cycloalkyl, halo, alkoxy-alkyl-, alkyl-O—C(O)—, cycloalkyl-alkyl-,dialkylamino-alkoxy-, and dialkylamino-alkyl-;

wherein R₅, R₆, R₇, R₈ and R₉ are independently alkyl or aryl, each ofwhich is optionally substituted by one to five substituents selectedfrom the group consisting of (C₁-C₇) alkyl, halo, hydroxy, (C₁-C₇)alkoxy, and aryl;

R₂ and R₃ are hydrogen;

X is selected from hydrogen, cyano, halogen, nitro, alkyl-S—,alkyl-SO₂—, H₂N—SO₂—, R₅—C(O)—, alkyl, or R₄—O, wherein R₄ and R₅ areindependently alkyl or aryl each of which is optionally substituted bysubstituents selected from the group consisting of (C₁-C₇) alkyl, halo,hydroxy, (C₁-C₇) alkoxy, and aryl;

Y is C or N; or

a pharmaceutically acceptable salt thereof, or an optical isomerthereof; or a mixture of optical isomers.

Preferably, the present invention provides the compound of formula(III), wherein R′₁ is selected from hydrogen, (C₁-C₄) alkyl, (C₆-C₁₂)aryl, (5-9) membered heteroaryl, (C₃-C₇) cycloalkyl-(C₁-C₄) alkyl-, eachof which is optionally substituted by one or two substituents selectedfrom the group consisting of (C₁-C₄) (C₁-C₄) alkyl-C(O)—, (5-9)membered-heterocycloalkyl-(C₁-C₄) alkyl-, (C₁-C₄) alkyl-(C₁-C₄) alkoxy-,(C₁-C₄) alkoxy-, (C₁-C₄) alkyl, (C₃-C₇) cycloalkyl, halogen, (C₁-C₄)alkoxy-(C₁-C₄) alkyl-, (C₁-C₄) alkyl-O—C(O)—, (C₁-C₄)dialkylamino-(C₁-C₄) alkoxy-, and (C₁-C₄) dialkylamino-(C₁-C₄) alkyl-;

R₂ and R₃ are hydrogen;

X is hydrogen, halogen, or (C₁-C₇) alkyl; or

a pharmaceutically acceptable salt thereof, or an optical isomerthereof; or a mixture of optical isomers.

Also preferably, the present invention provides the compound of formula(III), wherein R′₁ is hydrogen, (C₁-C₄) alkyl, phenyl, pyridine, saidpyridine is optionally substituted by one or two substituents selectedfrom (C₃-C₇) cycloalkyl, (C₁-C₄) alkyl, halo, (C₁-C₄) alkoxy-(C₁-C₄)alkyl-, (5-9) membered-heterocycloalkyl-(C₁-C₄) alkyl-, (5-9)membered-heterocycloalkyl-(C₁-C₄) alkoxy-, and (C₁-C₄)dialkylamino-(C₁-C₄) alkyl-; R₂ and R₃ are hydrogen; X is halogen; Y isC or N; or a pharmaceutically acceptable salt thereof, or an opticalisomer thereof; or a mixture of optical isomers.

The present invention provides for compounds of formula I, II and III,and pharmaceutical compositions employing such compounds and for methodsof using such compounds.

For purposes of interpreting this specification, the followingdefinitions will apply and whenever appropriate, terms used in thesingular will also include the plural and vice versa.

As used herein, the term “alkyl” refers to a fully saturated branched orunbranched hydrocarbon moiety. Preferably the alkyl comprises 1 to 20carbon atoms, more preferably 1 to 16 carbon atoms, 1 to 10 carbonatoms, 1 to 7 carbon atoms, or 1 to 4 carbon atoms. Representativeexamples of alkyl include, but are not limited to, methyl, ethyl,n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl,n-decyl and the like.

The term “aryl” refers to monocyclic or bicyclic aromatic hydrocarbongroups having 6-20 carbon atoms in the ring portion. Preferably, thearyl is a (C₆-C₁₂) aryl. Non-limiting examples include phenyl, biphenyl,naphthyl or tetrahydronaphthyl, each of which may optionally besubstituted by 1-4 substituents, such as optionally substituted alkyl,trifluoromethyl, cycloalkyl, halo, hydroxy, alkoxy, acyl, aryl-O—,heteroaryl-O—, optionally substituted amino, thiol, alkylthio, arylthio,nitro, cyano, carboxy, alkyl-O—C(O)—, carbamoyl, alkylthiono, sulfonyl,sulfonamido, heterocycloalkyl and the like.

Furthermore, the term “aryl” as used herein, refers to an aromaticsubstituent which can be a single aromatic ring, or multiple aromaticrings that are fused together, linked covalently, or linked to a commongroup such as a methylene or ethylene moiety. The common linking groupalso can be a carbonyl as in benzophenone or oxygen as in diphenyletheror nitrogen as in diphenylamine.

As used herein, the term “carbamoyl” refers to H₂NC(O)—, alkyl-NHC(O)—,(alkyl)₂NC(O)—, aryl-NHC(O)—, alkyl(aryl)-NC(O)—, heteroaryl-NHC(O)—,alkyl(heteroaryl)-NC(O)—, aryl-alkyl-NHC(O)—, alkyl(aryl-alkyl)-NC(O)—and the like.

As used herein, the term “sulfonamido” refers to alkyl-S(O)₂—NH—,aryl-S(O)₂—NH—, aryl-alkyl-S(O)₂—NH—, heteroaryl-S(O)₂—NH—,heteroaryl-alkyl-S(O)₂—NH—, alkyl-S(O)₂—N(alkyl)-, aryl-S(O)₂—N(alkyl)-,aryl-alkyl-S(O)₂—N(alkyl)-, heteroaryl-S(O)₂—N(alkyl)-,heteroaryl-alkyl-S(O)₂—N(alkyl)- and the like.

As used herein, the term “heterocycloalkyl” or “heterocyclo” refers toan optionally substituted, fully saturated, partially saturated, orunsaturated, aromatic or nonaromatic heterocyclic group, e.g., which isa 4- to 7-membered monocyclic, 7- to 12-membered bicyclic or 10- to15-membered tricyclic ring system, which can be fused, pedant, or spiro,and has at least one heteroatom in at least one carbon atom-containingring. Each ring of the heterocyclic group containing a heteroatom mayhave 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and sulfuratoms, where the —CH₂— on the ring can be replaced with a —C(O)— group,and sulfur heteroatom can also optionally be oxidized to S(O) or S(O)₂groups. In the fused ring system, one ring can be nonaromaticheterocyclic ring, and the other ring(s) can be cycloalkyl, aryl, orheteroaryl. The heterocyclic group may be attached at a heteroatom or acarbon atom.

Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl,pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl,imidazolidinyl, triazolyl, oxazolyl, oxazolidinyl, isoxazolinyl,isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl,isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl,piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl,thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone,1,3-dioxolane and tetrahydro-1,1-dioxothienyl,1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl and the like.

Exemplary bicyclic heterocyclic groups include indolyl, dihydroindolyl,benzothiazolyl, benzoxazinyl, benzoxazolyl, benzothienyl,benzothiazinyl, quinuclidinyl, quinolinyl, tetrahydroquinolinyl,decahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl,decahydroisoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl,benzofuryl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl,quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such asfuro[2,3-c]pyridinyl, furo[3,2-b]-pyridinyl] or furo[2,3-b]pyridinyl),dihydroisoindolyl, 1,3-dioxo-1,3-dihydroisoindol-2-yl,dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl),phthalazinyl and the like.

Exemplary tricyclic heterocyclic groups include carbazolyl,dibenzoazepinyl, dithienoazepinyl, benzindolyl, phenanthrolinyl,acridinyl, phenanthridinyl, phenoxazinyl, phenothiazinyl, xanthenyl,carbolinyl and the like.

As used herein, the term “sulfonyl” refers to R—SO₂—, wherein R ishydrogen, alkyl, aryl, heteroaryl, aryl-alkyl, heteroaryl-alkyl,aryl-O—, heteroaryl-O—, alkoxy, aryloxy, cycloalkyl, orheterocycloalkyl.

As used herein, the term “alkoxy” refers to alkyl-O—, wherein alkyl isdefined herein above. Representative examples of alkoxy include, but arenot limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy,tert-butoxy, pentyloxy, hexyloxy, cyclopropyloxy-, cyclohexyloxy- andthe like. As used herein, the term “lower alkoxy” refers to the alkoxygroups having about 1-7 preferably about 1-4 carbons.

As used herein, the term “acyl” refers to a group R—C(O)— of from 1 to10 carbon atoms of a straight, branched, or cyclic configuration or acombination thereof, attached to the parent structure through carbonylfunctionality. Such group may be saturated or unsaturated, and aliphaticor aromatic. Preferably, R in the acyl residue is alkyl, or alkoxy, oraryl, or heteroaryl. Also preferably, one or more carbons in the acylresidue may be replaced by nitrogen, oxygen or sulfur as long as thepoint of attachment to the parent remains at the carbonyl. Examplesinclude but are not limited to, acetyl, benzoyl, propionyl, isobutyryl,tert-butoxycarbonyl, benzyloxycarbonyl and the like. Lower acyl refersto acyl containing one to four carbons.

As used herein, the term “cycloalkyl” refers to optionally substitutedsaturated or unsaturated monocyclic, bicyclic or tricyclic hydrocarbongroups of 3-12 carbon atoms, each of which may be substituted by one ormore substituents, such as alkyl, halo, oxo, hydroxy, alkoxy,alkyl-C(O)—, acylamino, carbamoyl, alkyl-NH—, (alkyl)₂N—, thiol,alkylthio, nitro, cyano, carboxy, alkyl-O—C(O)—, sulfonyl, sulfonamido,sulfamoyl, heterocycloalkyl and the like. Exemplary monocyclichydrocarbon groups include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl andthe like. Exemplary bicyclic hydrocarbon groups include bornyl, indyl,hexahydroindyl, tetrahydronaphthyl, decahydronaphthyl,bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl,6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl,bicyclo[2.2.2]octyl and the like. Exemplary tricyclic hydrocarbon groupsinclude adamantyl and the like.

As used herein, the term “sulfamoyl” refers to H₂NS(O)₂—,alkyl-NHS(O)₂—, (alkyl)₂NS(O)₂—, aryl-NHS(O)₂—, alkyl(aryl)-NS(O)₂—,(aryl)₂NS(O)₂—, heteroaryl-NHS(O)₂—, aralkyl-NHS(O)₂—,heteroaralkyl-NHS(O)₂— and the like.

As used herein, the term “aryloxy” refers to both an —O-aryl and an —O—heteroaryl group.

As used herein, the term acylamino refers to the group —NRC(O)R′ whereeach of R and R′ is independently hydrogen, alkyl, aryl, heteroaryl, orheterocycloalkyl, where both R and R′ groups are optionally joined toform a heterocyclic group (e.g., morpholino) wherein alkyl, aryl,heteroaryl and heterocycloalkyl are as defined herein.

As used herein, the term “heteroaryl” refers to a 5-14 memberedmonocyclic- or bicyclic- or fused polycyclic-aromatic ring system,having 1 to 8 heteroatoms selected from N, O or S. Preferably, theheteroaryl is a 5-10 membered aromatic ring system. Typical heteroarylgroups include 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 4-,or 5-imidazolyl, 3-, 4-, or 5-pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-,or 5-isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or5-1,2,4-triazolyl, 4- or 5-1,2,3-triazolyl, tetrazolyl, 2-, 3-, or4-pyridyl, 3- or 4-pyridazinyl, 3-, 4-, or 5-pyrazinyl, 2-pyrazinyl, 2-,4-, or 5-pyrimidinyl.

The term “heteroaryl” also refers to a group in which a heteroaromaticring is fused to one or more aryl, cycloalkyl, or heterocycloalkylrings, where the radical or point of attachment is on the heteroaromaticring. Nonlimiting examples include but are not limited to 1-, 2-, 3-,5-, 6-, 7-, or 8-indolizinyl, 1-, 3-, 4-, 5-, 6-, or 7-isoindolyl, 2-,3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-indazolyl, 2-,4-, 5-, 6-, 7-, or 8-purinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or9-quinolizinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinoliyl, 1-, 3-, 4-, 5-,6-, 7-, or 8-isoquinoliyl, 1-, 4-, 5-, 6-, 7-, or 8-phthalazinyl, 2-,3-, 4-, 5-, or 6-naphthyridinyl, 2-, 3-, 5-, 6-, 7-, or 8-quinazolinyl,3-, 4-, 5-, 6-, 7-, or 8-cinnolinyl, 2-, 4-, 6-, or 7-pteridinyl, 1-,2-, 3-, 4-, 5-, 6-, 7-, or 8-4-aH carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-,7-, or 8-carbazolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-carbolinyl, 1-,2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenanthridinyl, 1-, 2-, 3-, 4-, 5-,6-, 7-, 8-, or 9-acridinyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or9-perimidinyl, 2-, 3-, 4-, 5-, 6-, 8-, 9-, or 10-phenathrolinyl, 1-, 2-,3-, 4-, 6-, 7-, 8-, or 9-phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or10-phenothiazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenoxazinyl,2-, 3-, 4-, 5-, 6-, or 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, or10-benzisoqinolinyl, 2-, 3-, 4-, or thieno[2,3-b]furanyl, 2-, 3-, 5-,6-, 7-, 8-, 9-, 10-, or 11-7H-pyrazino[2,3-c]carbazolyl, 2-, 3-, 5-, 6-,or 7-2H-furo[3,2-b]-pyranyl, 2-, 3-, 4-, 5-, 7-, or8-5H-pyrido[2,3-d]-o-oxazinyl, 1-, 3-, or 5-1H-pyrazolo[4,3-d]-oxazolyl,2-, 4-, or 5-4H-imidazo[4,5-d]thiazolyl, 3-, 5-, or8-pyrazino[2,3-d]pyridazinyl, 2-, 3-, 5-, or 6-imidazo[2,1-b]thiazolyl,1-, 3-, 6-, 7-, 8-, or 9-furo[3,4-c]cinnolinyl, 1-, 2-, 3-, 4-, 5-, 6-,8-, 9-, 10, or 11-4H-pyrido[2,3-c]carbazolyl, 2-, 3-, 6-, or7-imidazo[1,2-b][1,2,4]triazinyl, 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 4-, 5-, 6-,or 7-benzothiazolyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or 9-benzoxapinyl, 2-,4-, 5-, 6-, 7-, or 8-benzoxazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-,or 11-1H-pyrrolo[1,2-b][2]benzazapinyl. Typical fused heteroaryl groupsinclude, but are not limited to 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl,1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 5-, 6-, or7-benzothiazolyl.

A heteroaryl group may be mono-, bi-, tri-, or polycyclic, preferablymono-, bi-, or tricyclic, more preferably mono- or bicyclic.

As used herein, the term “halo” refers to fluoro, chloro, bromo, andiodo.

As used herein, the term “isomers” refers to different compounds thathave the same molecular formula. Also as used herein, the term “anoptical isomer” refers to any of the various stereo isomericconfigurations which may exist for a given compound of the presentinvention and includes geometric isomers. It is understood that asubstituent may be attached at a chiral center of a carbon atom.Therefore, the invention includes enantiomers, diastereomers orracemates of the compound. “Enantiomers” are a pair of stereoisomersthat are non-superimposable mirror images of each other. A 1:1 mixtureof a pair of enantiomers is a “racemic” mixture. The term is used todesignate a racemic mixture where appropriate. “Diastereoisomers” arestereoisomers that have at least two asymmetric atoms, but which are notmirror-images of each other. The absolute stereochemistry is specifiedaccording to the Cahn-Ingold-Prelog R-S system. When a compound is apure enantiomer the stereochemistry at each chiral carbon may bespecified by either R or S. Resolved compounds whose absoluteconfiguration is unknown can be designated (+) or (−) depending on thedirection (dextro- or levorotatory) which they rotate plane polarizedlight at the wavelength of the sodium D line. Certain of the compoundsdescribed herein contain one or more asymmetric centers and may thusgive rise to enantiomers, diastereomers, and other stereoisomeric formsthat may be defined, in terms of absolute stereochemistry, as (R)- or(S)-. The present invention is meant to include all such possibleisomers, including racemic mixtures, optically pure forms andintermediate mixtures. Optically active (R)- and (S)-isomers may beprepared using chiral synthons or chiral reagents, or resolved usingconventional techniques. If the compound contains a double bond, thesubstituent may be E or Z configuration. If the compound contains adisubstituted cycloalkyl, the cycloalkyl substituent may have a cis- ortrans-configuration. All tautomeric forms are also intended to beincluded.

As used herein, the term “pharmaceutically acceptable salts” refers tosalts that retain the biological effectiveness and properties of thecompounds of this invention and, which are not biologically or otherwiseundesirable. In many cases, the compounds of the present invention arecapable of forming acid and/or base salts by virtue of the presence ofamino and/or carboxyl groups or groups similar thereto. Pharmaceuticallyacceptable acid addition salts can be formed with inorganic acids andorganic acids. Inorganic acids from which salts can be derived include,for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitricacid, phosphoric acid, and the like. Organic acids from which salts canbe derived include, for example, acetic acid, propionic acid, glycolicacid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinicacid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamicacid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceuticallyacceptable base addition salts can be formed with inorganic and organicbases. Inorganic bases from which salts can be derived include, forexample, sodium, potassium, lithium, ammonium, calcium, magnesium, iron,zinc, copper, manganese, aluminum, and the like; particularly preferredare the ammonium, potassium, sodium, calcium and magnesium salts.Organic bases from which salts can be derived include, for example,primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, basic ionexchange resins, and the like, specifically such as isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine, andethanolamine. The pharmaceutically acceptable salts of the presentinvention can be synthesized from a parent compound, a basic or acidicmoiety, by conventional chemical methods. Generally, such salts can beprepared by reacting free acid forms of these compounds with astoichiometric amount of the appropriate base (such as Na, Ca, Mg, or Khydroxide, carbonate, bicarbonate, or the like), or by reacting freebase forms of these compounds with a stoichiometric amount of theappropriate acid. Such reactions are typically carried out in water orin an organic solvent, or in a mixture of the two. Generally,non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, oracetonitrile are preferred, where practicable. Lists of additionalsuitable salts can be found, e.g., in Remington's PharmaceuticalSciences, 20th ed., Mack Publishing Company, Easton, Pa., (1985), whichis herein incorporated by reference.

As used herein, the term “pharmaceutically acceptable carrier” includesany and all solvents, dispersion media, coatings, surfactants,antioxidants, preservatives (e.g., antibacterial agents, antifungalagents), isotonic agents, absorption delaying agents, salts,preservatives, drugs, drug stabilizers, binders, excipients,disintegration agents, lubricants, sweetening agents, flavoring agents,dyes, such like materials and combinations thereof, as would be known toone of ordinary skill in the art (see, for example, Remington'sPharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp.1289-1329, incorporated herein by reference). Except insofar as anyconventional carrier is incompatible with the active ingredient, its usein the therapeutic or pharmaceutical compositions is contemplated.

The term “therapeutically effective amount” of a compound of the presentinvention refers to an amount of the compound of the present inventionthat will elicit the biological or medical response of a subject, orameliorate symptoms, slow or delay disease progression, or prevent adisease, etc. In a preferred embodiment, the “effective amount” refersto the amount that inhibits or reduces expression or activity of MMP-2,and/or MMP-8, and/or MMP-9, and/or MMP-12, and/or MMP-13.

As used herein, the term “subject” refers to an animal. Preferably, theanimal is a mammal. A subject also refers to for example, primates(e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats,mice, fish, birds and the like. In a preferred embodiment, the subjectis a human.

As used herein, the term “a disorder” or “a disease” refers to anyderangement or abnormality of function; a morbid physical or mentalstate. See Dorland's Illustrated Medical Dictionary, (W.B. Saunders Co.27th ed. 1988).

As used herein, the term “inhibition” or “inhibiting” refers to thereduction or suppression of a given condition, symptom, or disease, or asignificant decrease in the baseline activity of a biological activityor process. Preferably, the condition is associated with or mediated byMMP-2, and/or MMP-8, and/or MMP-9, and/or MMP-12, and/or MMP-13.

As used herein, the term “treating” or “treatment” of any disease ordisorder refers in one embodiment, to ameliorating the disease ordisorder (i.e., arresting or reducing the development of the disease orat least one of the clinical symptoms thereof). In another embodiment“treating” or “treatment” refers to ameliorating at least one physicalparameter, which may not be discernible by the patient. In yet anotherembodiment, “treating” or “treatment” refers to modulating the diseaseor disorder, either physically, (e.g., stabilization of a discerniblesymptom), physiologically, (e.g., stabilization of a physicalparameter), or both. In yet another embodiment, “treating” or“treatment” refers to preventing or delaying the onset or development orprogression of the disease or disorder.

As used herein, the term “a,” “an,” “the” and similar terms used in thecontext of the present invention (especially in the context of theclaims) are to be construed to cover both the singular and plural unlessotherwise indicated herein or clearly contradicted by the context.Recitation of ranges of values herein is merely intended to serve as ashorthand method of referring individually to each separate valuefalling within the range. Unless otherwise indicated herein, eachindividual value is incorporated into the specification as if it wereindividually recited herein. All methods described herein can beperformed in any suitable order unless otherwise indicated herein orotherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (e.g. “such as”) provided herein isintended merely to better illuminate the invention and does not pose alimitation on the scope of the invention otherwise claimed. No languagein the specification should be construed as indicating any non-claimedelement essential to the practice of the invention.

Any asymmetric carbon atom on the compounds of the present invention canbe present in the (R)-, (S)- or (R,S)-configuration, preferably in the(R)- or (S)-configuration. Substituents at atoms with unsaturated bondsmay, if possible, be present in cis- (Z)- or trans (E)-form. Therefore,the compounds of the present invention can be in the form of one of thepossible isomers or mixtures thereof, for example, as substantially puregeometric (cis or trans) isomers, diastereomers, optical isomers(antipodes), racemates or mixtures thereof.

Any resulting mixtures of isomers can be separated on the basis of thephysicochemical differences of the constituents, into the pure geometricor optical isomers, diastereomers, racemates, for example, by silica gelchromatography and/or fractional crystallization.

Any resulting racemates of final products or intermediates can beresolved into the optical antipodes by known methods, e.g., byseparation of the diastereomeric salts thereof, obtained with anoptically active acid or base, and liberating the optically activeacidic or basic compound.

The invention includes pharmaceutically acceptable isotopically-labelledcompounds of formula (I) wherein one or more atoms are replaced by atomshaving the same atomic number, but an atomic mass or mass numberdifferent from the atomic mass or mass number usually found in nature.

Examples of isotopes suitable for inclusion in the compounds of theinvention include isotopes of hydrogen, such as ²H and ³H, carbon, suchas ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶Cl, fluorine, such as ¹⁸F,iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as ¹³N and ¹⁵N, oxygen,such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P, and sulphur, such as³⁵S. Certain isotopically-labelled compounds of formula (I), forexample, those incorporating a radioactive isotope, are useful in drugand/or substrate tissue distribution studies. The radioactive isotopes³H and ¹⁴C are particularly useful for this purpose in view of theirease of incorporation and ready means of detection. Substitution withpositron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and ¹³N, can be usefulin Positron Emission Topography (PET) studies for examining substratereceptor occupancy. Isotopically-labelled compounds of formula (I) cangenerally be prepared by conventional techniques known to those skilledin the art or by processes analogous to those described herein using anappropriate isotopically-labelled reagent in place of the non-labelledreagent previously employed.

Finally, compounds of the present invention are either obtained in thefree form, as a salt thereof, or as prodrug derivatives thereof.

When a basic group is present in the compounds of the present invention,the compounds can be converted into acid addition salts thereof, inparticular, acid addition salts with the imidazolyl moiety of thestructure, preferably pharmaceutically acceptable salts thereof. Theseare formed, with inorganic acids or organic acids. Suitable inorganicacids include but are not limited to, hydrochloric acid, sulfuric acid,a phosphoric or hydrohalic acid. Suitable organic acids include but arenot limited to, carboxylic acids, such as (C₁-C₄) alkanecarboxylic acidswhich, for example, are unsubstituted or substituted by halogen, e.g.,acetic acid, such as saturated or unsaturated dicarboxylic acids, e.g.,oxalic, succinic, maleic or fumaric acid, such as hydroxycarboxylicacids, e.g., glycolic, lactic, malic, tartaric or citric acid, such asamino acids, e.g., aspartic or glutamic acid, organic sulfonic acids,such as (C₁-C₄) alkylsulfonic acids, e.g., methanesulfonic acid; orarylsulfonic acids which are unsubstituted or substituted, e.g., byhalogen. Preferred are salts formed with hydrochloric acid,methanesulfonic acid and maleic acid.

When an acidic group is present in the compounds of the presentinvention, the compounds can be converted into salts withpharmaceutically acceptable bases. Such salts include alkali metalsalts, like sodium, lithium and potassium salts; alkaline earth metalsalts, such as calcium and magnesium salts; ammonium salts with organicbases, e.g., trimethylamine salts, diethylamine salts, tris(hydroxymethyl)methylamine salts, dicyclohexylamine salts andN-methyl-D-glucamine salts; salts with amino acids such as arginine,lysine and the like. Salts may be formed using conventional methods,advantageously in the presence of an ethereal or alcoholic solvent, suchas a lower alkanol. From the solutions of the latter, the salts may beprecipitated with ethers, e.g., diethyl ether. Resulting salts may beconverted into the free compounds by treatment with acids. These orother salts can also be used for purification of the compounds obtained.

When both a basic group and an acid group are present in the samemolecule, the compounds of the present invention can also form internalsalts.

The present invention also provides pro-drugs of the compounds of thepresent invention that converts in vivo to the compounds of the presentinvention. A pro-drug is an active or inactive compound that is modifiedchemically through in vivo physiological action, such as hydrolysis,metabolism and the like, into a compound of this invention followingadministration of the prodrug to a subject. The suitability andtechniques involved in making and using pro-drugs are well known bythose skilled in the art. Prodrugs can be conceptually divided into twonon-exclusive categories, bioprecursor prodrugs and carrier prodrugs.See The Practice of Medicinal Chemistry, Ch. 31-32 (Ed. Wermuth,Academic Press, San Diego, Calif., 2001). Generally, bioprecursorprodrugs are compounds are inactive or have low activity compared to thecorresponding active drug compound, that contains one or more protectivegroups and are converted to an active form by metabolism or solvolysis.Both the active drug form and any released metabolic products shouldhave acceptably low toxicity. Typically, the formation of active drugcompound involves a metabolic process or reaction that is one of thefollow types:

1. Oxidative reactions, such as oxidation of alcohol, carbonyl, and acidfunctions, hydroxylation of aliphatic carbons, hydroxylation ofalicyclic carbon atoms, oxidation of aromatic carbon atoms, oxidation ofcarbon-carbon double bonds, oxidation of nitrogen-containing functionalgroups, oxidation of silicon, phosphorus, arsenic, and sulfur, oxidativeN-delakylation, oxidative O- and S-delakylation, oxidative deamination,as well as other oxidative reactions.

2. Reductive reactions, such as reduction of carbonyl groups, reductionof alcoholic groups and carbon-carbon double bonds, reduction ofnitrogen-containing functions groups, and other reduction reactions.

3. Reactions without change in the state of oxidation, such ashydrolysis of esters and ethers, hydrolytic cleavage of carbon-nitrogensingle bonds, hydrolytic cleavage of non-aromatic heterocycles,hydration and dehydration at multiple bonds, new atomic linkagesresulting from dehydration reactions, hydrolytic dehalogenation, removalof hydrogen halide molecule, and other such reactions.

Carrier prodrugs are drug compounds that contain a transport moiety,e.g., that improve uptake and/or localized delivery to a site(s) ofaction. Desirably for such a carrier prodrug, the linkage between thedrug moiety and the transport moiety is a covalent bond, the prodrug isinactive or less active than the drug compound, and any releasedtransport moiety is acceptably non-toxic. For prodrugs where thetransport moiety is intended to enhance uptake, typically the release ofthe transport moiety should be rapid. In other cases, it is desirable toutilize a moiety that provides slow release, e.g., certain polymers orother moieties, such as cyclodextrins. See, Cheng et al., US20040077595,application Ser. No. 10/656,838. Such carrier prodrugs are oftenadvantageous for orally administered drugs. Carrier prodrugs can, forexample, be used to improve one or more of the following properties:increased lipophilicity, increased duration of pharmacological effects,increased site-specificity, decreased toxicity and adverse reactions,and/or improvement in drug formulation (e.g., stability, watersolubility, suppression of an undesirable organoleptic or physiochemicalproperty). For example, lipophilicity can be increased by esterificationof hydroxyl groups with lipophilic carboxylic acids, or of carboxylicacid groups with alcohols, e.g., aliphatic alcohols. Wermuth, ThePractice of Medicinal Chemistry, Ch. 31-32, Ed. Werriuth, AcademicPress, San Diego, Calif., 2001.

Exemplary prodrugs are, e.g., esters of free carboxylic acids and S-acyland O-acyl derivatives of thiols, alcohols or phenols, wherein acyl hasa meaning as defined herein. Preferred are pharmaceutically acceptableester derivatives convertible by solvolysis under physiologicalconditions to the parent carboxylic acid, e.g., lower alkyl esters,cycloalkyl esters, lower alkenyl esters, benzyl esters, mono- ordi-substituted lower alkyl esters, such as the ω-(amino, mono- ordi-lower alkylamino, carboxy, lower alkoxycarbonyl)-lower alkyl esters,the α-(lower alkanoyloxy, lower alkoxycarbonyl or di-loweralkylaminocarbonyl)-lower alkyl esters, such as the pivaloyloxymethylester and the like conventionally used in the art. In addition, amineshave been masked as arylcarbonyloxymethyl substituted derivatives whichare cleaved by esterases in vivo releasing the free drug andformaldehyde (Bundgaard, J. Med. Chem. 2503 (1989)). Moreover, drugscontaining an acidic NH group, such as imidazole, imide, indole and thelike, have been masked with N-acyloxymethyl groups (Bundgaard, Design ofProdrugs, Elsevier (1985)). Hydroxy groups have been masked as estersand ethers. EP 039,051 (Sloan and Little) discloses Mannich-basehydroxamic acid prodrugs, their preparation and use.

In view of the close relationship between the compounds, the compoundsin the form of their salts and the pro-drugs, any reference to thecompounds of the present invention is to be understood as referring alsoto the corresponding pro-drugs of the compounds of the presentinvention, as appropriate and expedient.

Furthermore, the compounds of the present invention, including theirsalts, can also be obtained in the form of their hydrates, or includeother solvents used for their crystallization.

The compounds of the present invention have valuable pharmacologicalproperties, they are useful as inhibitors of matrix metalloproteinasessuch as matrix metalloproteinase 2 (MMP-2), matrix metalloproteinase 8(MMP-8), matrix metalloproteinase 9 (MMP-9), matrix metalloproteinase 12(MMP-12) and matrix metalloproteinase 13 (MMP-13). MMP-2 and MMP-9 aregelatinases involved in tissue remodeling and both have been implicatedin aiding the tumor metastasis process. As such, selective inhibition ofthese gelatinase proteases may be useful in the treatment of metastatictumors. MMP-8, also known as collagenase-2 or neutrophil collagenase, isalso involved in tissue remodeling. Inhibition of MMP-8 is useful forthe prevention, delay of progression, or treatment of diseases such asfibrotic diseases of the lung, degradative diseases such as pulmonaryemphysema, and osteoarthritis, etc. MMP-12, also known as macrophageelastase or metalloelastase, is able to degrade extracellular matrixcomponents such as elastin and is involved in tissue remodelingprocesses. MMP-12 has been indicated to be a key protein in thepathologenesis of tumor invasineness, arthritis, atherosclerosis, Alportsyndrome, and chromical obstructive pulmonary disease (COPD). MMP-13,also known as collagenase 3, has been indicated in (1) extracellularmatrix degradation and cell-matrix interaction associated withmetastasis especially as observed in invasive breast cancer lesions andin malignant epithelia growth in skin carcinogenesis; and (2) duringprimary ossification and skeletal remodelling (M. Stahle-Backdahl etal., (1997) Lab. Invest. 76 (5):717-728; N. Johansson et al., (1997)Dev. Dyn. 208(3):387-397), in destructive joint diseases such asrheumatoid and osteo-arthritis (D. Wernicke et al., (1996) J. Rheumatol.23:590-595; P. G. Mitchell et al., (1996) J. Clin. Invest.97(3):761-768; O. Lindy et al., (1997) Arthritis Rheum. 40(8:1391-1399);and the aseptic loosening of hip replacements (S. Imai et al., (1998) J.Bone Joint Surg. Br. 80(4):701-710). MMP13 has also been implicated inchronic adult periodontitis as it has been localised to the epitheliumof chronically inflamed mucosa human gingival tissue (V. J. Uitto etal., (1998) Am. J. Pathol. 152(6):1489-1499) and in remodelling of thecollagenous matrix in chronic wounds (M. Vaalamo et al., (1997) J.Invest. Dermatol. 109(1): 96-101).

Accordingly, the compounds of the present invention are also useful fortreatment of a disorder or a disease mediated by MMP-2, and/or MMP-8,and/or MMP-9, and/or MMP-12, and/or MMP-13. In particular, the compoundsof the present invention are useful for treatment of at least onedisorder or disease selected from Alport syndrome, asthma, rhinitis,chronic obstructive pulmonary diseases (COPD), arthritis (such asrheumatoid arthritis and osteoarthritis), atherosclerosis andrestenosis, cancer invasion and metastasis, diseases involving tissuedestruction, loosening of hip joint replacements, periodontal disease,fibrotic disease, infarction and heart disease, liver and renalfibrosis, endometriosis, diseases related to the weakening of theextracellular matrix, heart failure, aortic aneurysms, CNS relateddiseases such as Alzheimer's disease and Multiple Sclerosis (MS),hematological disorders.

Additionally, the present invention provides:

-   -   a compound of the present invention for use as a medicament;    -   the use of a compound of the present invention for the        preparation of a pharmaceutical composition for the delay of        progression and/or treatment of a disorder or disease mediated        by MMP-2, and/or MMP-8, and/or MMP-9, and/or MMP-12, and/or        MMP-13.    -   the use of a compound of the present invention for the        preparation of a pharmaceutical composition for the delay of        progression and/or treatment of a disorder or disease mediated        by MMP-2, and/or MMP-8, and/or MMP-9, and/or MMP-12, and/or        MMP-13.    -   the use of a compound of the present invention for the        preparation of a pharmaceutical composition for the delay of        progression and/or treatment of a disorder or disease selected        from Alport syndrome, asthma, rhinitis, chronic obstructive        pulmonary diseases (COPD), arthritis (such as rheumatoid        arthritis and osteoarthritis), atherosclerosis and restenosis,        cancer invasion and metastasis, diseases involving tissue        destruction, loosening of hip joint replacements, periodontal        disease, fibrotic disease, infarction and heart disease, liver        and renal fibrosis, endometriosis, diseases related to the        weakening of the extracellular matrix, heart failure, aortic        aneurysms, CNS related diseases such as Alzheimer's disease and        Multiple Sclerosis (MS), hematological disorders.

The compounds of formula (I) and (II) can be prepared by any of fourgeneral ketone synthesis procedures described in the following section.

The first method (method A) is the construction of the ketone by FriedelCrafts acylation, as in the following example:

Typical Procedure for the Synthesis of Benzoyl Chlorides4-Chloro-3-sulfamoyl-benzoyl chloride

A mixture of 4-chloro-3-sulfamoyl-benzoic acid (50 g, 212 mmol) andthionyl chloride (31 mL, 424 mmol) are heated to reflux for 5 h thenallowed to cool to room temperature. To this mixture is added hexane andthe resulting solid is filtered, washed with hexane and dried in vacuoto yield 52.3 g (97%) of the title compound as an off-white solid.

Typical Procedure for the Formation of Ketones by Friedel CraftsAcylation

The requisite ketone may be generated by mixing the coupling partners inmethylene chloride (dichloromethane) or 1,2-dichloroethane andintroducing a Lewis acid (aluminium chloride, MeAlCl₂ or Me₂AlCl) topromote acylium ion formation which undergoes the Friedel Craftsacylation.

The second method (method B) involves the addition of an organometallicreagent to an aldehyde and subsequent oxidation of the resultant alcoholto the ketone. Typically, the requisite aldehyde(2-chloro-5-formyl-benzenesulfonamide), is synthesized as shown below.

General Procedure for the Synthesis of2-chloro-5-formyl-benzenesulfonamide 4-Chloro-3-sulfamoyl-benzoic acidethyl ester

To a suspension of 4-chloro-3-sulfamoyl-benzoic acid (50 g, 212 mmol) in500 mL ethanol is bubbled HCl gas for 10 minutes. The resultingsuspension is then heated at reflux for 16 h, cooled and concentrated invacuo. The resulting residue is recrystallized from isopronanol to yield55.9 g (99%) of the title compound as an off-white solid.

2-Chloro-5-hydroxymethyl-benzenesulfonamide

To a solution of 4-chloro-3-sulfamoyl-benzoic acid ethyl ester (46.95 g,166 mmol) in 500 mL of dry tetrahydrofuran is added dropwise, withstirring, 199 mL of a 2 M solution of lithium borohydride intetrahydrofuran. The mixture is stirred and refluxed for 5 hr, then leftat room temperature for 18 h, and is then carefully diluted with 400 mLof water. The mixture is cooled to 4° C. for 24 hours and filtered toyield 32.7 g (82%) of the title compound as an off-white solid.

2-Chloro-5-formyl-benzenesulfonamide

To a well stirred solution of2-chloro-5-hydroxymethyl-benzenesulfonamide (31.6 g, 143 mmol) in 300 mLtetrahydrofuran is added 62.0 g (713 mmol) of MnO₂. The resultingsolution is heated at reflux for 16 h, filtered through Celite thenthrough a 0.4 μM Teflon filter and the filtrate is concentrated in vacuoto remove the tetrahydrofuran. Trituration with hexanes provided 25 g(80%) of the title compound as a grey solid.

2-Chloro-5-(4-fluoro-benzoyl)-benzenesulfonamide

2-Chloro-5-[(4-fluoro-phenyl)-hydroxy-methyl]-benzenesulfonamide

A solution of 590 mg of 1-bromofluorobenzene (1.11 mmol, 3 equivalent)in 10 mL of anhydrous tetrahydrofuran is stirred at −78° C. as 3.9 mL oftert-butyllithium (1.7 M in cyclohexane, 6.66 mmol, 6 equivalent) isadded drop-wise. The reaction mixture is stirred at −78° C. for 2 h,then is transferred to a previously prepared a solution of 243 mg of 2chloro-5-formyl-benzenesulfonamide (1.11 mmol, 1 equivalent) and 0.65 mLof tert-butyllithium (1.7 M in cyclohexane, 1 equivalent) in 10 mL ofanhydrous tetrahydrofuran. The reaction is allowed to warm to roomtemperature and stirred at room temperature for 18 h. The reaction isquenched with 0.1 N HCl and then extracted several times with ethylacetate. The combined organic extracts are dried over sodium sulfate,and concentrated in vacuo to give 65 mg of the title compound which iscarried on without further purification.

2-Chloro-5-(4-fluoro-benzoyl)-benzenesulfonamide

A solution of 65 mg of2-chloro-5-((4-fluoro-phenyl)-hydroxy-methyl)-benzenesulfonamide in 1 mLof acetone is stirred at room temperature as 0.2 mL of 3 M Jones'reagent is added. The reaction mixture is stirred at room temperaturefor 30 minutes then diluted with ethyl acetate, filtered through celite,the filtrate is concentrated in vacuo. The crude product is purified bysilica gel chromatography to give 48 mg of the title compound as whitefoam. ¹H NMR (CDCl₃): 5.15 (br, 2H), 7.12-7.30 (m, 3H), 7.70 (d, J=8 Hz,1H), 7.80-7.90 (m, 2H), 7.90-8.0 (dd, 1H), 8.5 (d, J=2 Hz, 1H). MS(m/z): 312 (M−1).

In the third method (method C), ketone synthesis is accomplished usingan electrophilic Weinreb amide coupling partner in lieu of the aldehyde.

Typical Procedure for the Formation of the Weinreb Coupling PartnerPreparation of 4-chloro-N-methoxy-N-methyl-3-sulfamoyl-benzamide

4-Chloro-3-sulfamoyl-benzoic acid (5 g) is treated with 20.5 mL ofthionyl chloride and heated to reflux for 5.5 h. Thionyl chloride isremoved and the residue is dried at 50° C. in vacuo to give 5.6 g of4-chloro-3-sulfamoyl-benzoyl chloride as a tan powder. This material istaken up in 28 mL of methylene chloride and treated at 0° C. with 2.64 gof N,O-dimethylhydroxylamine hydrochloride followed by 10.9 mL ofpyridine and stirred overnight at room temperature. The reaction mixtureis quenched at 0° C. with 19 mL of 3 N aqueous HCl and extracted withethyl acetate. The organics are combined, washed with saturated aqueoussodium bicarbonate, 0.1 N aqueous HCl and a saturated sodium chloridesolution, dried over magnesium sulfate and concentrated in vacuo. Theresulting crystals are filtered through a short pad of silica gel (1:2hexanes/ethyl acetate) to give the title compound as a white powder. MS(m/z): (M−1) 277; Rf 0.36 (1:2 hexanes/ethyl acetate).

Typical Procedure for the Formation of Ketones Using Method C2-Chloro-5-(4-dimethylamino-benzoyl)-benzenesulfonamide

A solution of 1.07 g of N,N-dimethyl-4-bromoamine (5.39 mmol, 3equivalent) in 30 mL of anhydrous tetrahydrofuran is stirred at −78° C.as 6.34 mL of tert-butyllithium (1.7 M in pentane, 10.78 mmol, 6equivalent) is added. The reaction mixture is stirred at −78° C. for 10minutes, then 430 mg of4-chloro-N-methoxy-N-methyl-3-sulfamoyl-benzamide (1.54 mmol, 1equivalent) in 10 mL of anhydrous tetrahydrofuran is added. The reactionis stirred at −78° C. for 20 minutes, then warmed to room temperatureand stirred at room temperature for 18 h. The reaction is quenched withwater and extracted with ethyl acetate. The combined organic extractsare washed with a saturated sodium chloride solution, dried over sodiumsulfate, and concentrated in vacuo. After purification by flashchromatography, 300 mg of product is obtained as a solid (yield, 57%).¹H NMR (400 MHz, CDCl₃): δ 3.10 (s, 6H), 5.17 (s, 2H), 6.68 (d, 2H, J=12Hz), 7.64 (d, 1H, J=8 Hz), 7.74 (d, 2H, J=8 Hz), 7.86 (d, 1H, J=2 Hz),8.41 (s, 1H). MS (m/z): 339 (M+1).

In the fourth method (method D), ketone synthesis is accomplished usingpalladium cross coupling of an organostannane with an acid chloride.

Typical Procedure for Palladium Cross Coupling, Synthesis of IndazoleDerivatives

The bromo-indazole compound (1.0 equivalent) and hexamethylditin (1.25equivalent) are dissolved in deoxygenated toluene under a nitrogenatmosphere. Palladium tetrakis(triphenylphosphine) (0.07 equivalent) isadded, and the mixture is heated to reflux until LC-MS analysis showscomplete disappearance of the bromide. The reaction mixture is portionedbetween pH 7 buffer and ethyl acetate, and the combined organics aredried over sodium sulfate, and concentrated to provide crudearylstannane which is used without additional purification. Thearylstannane (1.0 equivalent) and 1,8-bis(dimethyl amino)naphthalene(0.5 equivalent) dissolved in tetrahydrofuran is treated with benzoylchloride (1.0 equivalent). After a few minutes, allylpalladium chloridedimer (0.05 equivalent) is added, the reaction mixture is stirred for 5min at ambient temperature and then refluxed for 2-18 h. After coolingto ambient temperature, the reaction is diluted with dichloromethane,washed with saturated aqueous sodium bicarbonate, and saturated aqueoussodium chloride. Drying with sodium sulfate, filtration, andconcentration gives a crude product, which is purified by flashchromatography to afford a beige solid.

One of ordinary skill in the art would appreciate that modifications ofthese general ketone synthetic schemes are possible without departingfrom the scope of the invention. It is also obvious to those skilled inthe art that other methods of ketone synthesis are available and thesefour methods are merely a sampling of strategies for ketone preparation.

In starting compounds and intermediates which are converted to thecompounds of the present invention in a manner described herein,functional groups present, such as amino, thiol, carboxyl and hydroxygroups, are optionally protected by conventional protecting groups thatare common in preparative organic chemistry. Protected amino, thiol,carboxyl and hydroxyl groups are those that can be converted under mildconditions into free amino thiol, carboxyl and hydroxyl groups withoutthe molecular framework being destroyed or other undesired sidereactions taking place.

The purpose of introducing protecting groups is to protect thefunctional groups from undesired reactions with reaction componentsunder the conditions used for carrying out a desired chemicaltransformation. The need and choice of protecting groups for aparticular reaction is known to those skilled in the art and depends onthe nature of the functional group to be protected (hydroxyl group,amino group, carboxy, etc.), the structure and stability of the moleculeof which the substituent is a part and the reaction conditions.

Well-known protecting groups that meet these conditions and theirintroduction and removal are described, e.g., in McOmie, “ProtectiveGroups in Organic Chemistry”, Plenum Press, London, N.Y. (1973); andGreene and Wuts, “Protective Groups in Organic Synthesis”, John Wileyand Sons, Inc., NY (1999).

The above-mentioned reactions are carried out according to standardmethods, in the presence or absence of diluent, preferably, such as areinert to the reagents and are solvents thereof, of catalysts, condensingor said other agents, respectively and/or inert atmospheres, at lowtemperatures, room temperature or elevated temperatures, preferably ator near the boiling point of the solvents used, and at atmospheric orsuper-atmospheric pressure. The preferred solvents, catalysts andreaction conditions are set forth in the appended illustrative examples.

The invention further includes any variant of the present processes, inwhich an intermediate product obtainable at any stage thereof is used asstarting material and the remaining steps are carried out, or in whichthe starting materials are formed in situ under the reaction conditions,or in which the reaction components are used in the form of their saltsor optically pure antipodes.

Compounds of the invention and intermediates can also be converted intoeach other according to methods generally known per se.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising a compound of the present invention and apharmaceutically acceptable carrier. The pharmaceutical composition canbe formulated for particular routes of administration such as oraladministration, parenteral administration, and rectal administration,etc. In addition, the pharmaceutical compositions of the presentinvention can be made up in a solid form including capsules, tablets,pills, granules, powders or suppositories, or in a liquid form includingsolutions, suspensions or emulsions. The pharmaceutical compositions canbe subjected to conventional pharmaceutical operations such assterilization and/or can contain conventional inert diluents,lubricating agents, or buffering agents, as well as adjuvants, such aspreservatives, stabilizers, wetting agents, emulsifiers and buffers etc.

Preferably, the pharmaceutical compositions are tablets and gelatincapsules comprising the active ingredient together with

-   -   a) diluents, e.g., lactose, dextrose, sucrose, mannitol,        sorbitol, cellulose and/or glycine;    -   b) lubricants, e.g., silica, talcum, stearic acid, its magnesium        or calcium salt and/or polyethyleneglycol; for tablets also    -   c) binders, e.g., magnesium aluminum silicate, starch paste,        gelatin, tragacanth, methylcellulose, sodium        carboxymethylcellulose and/or polyvinylpyrrolidone; if desired    -   d) disintegrants, e.g., starches, agar, alginic acid or its        sodium salt, or effervescent mixtures; and/or    -   e) absorbents, colorants, flavors and sweeteners.

Tablets may be either film coated or enteric coated according to methodsknown in the art.

Suitable compositions for oral administration include an effectiveamount of a compound of the invention in the form of tablets, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsion,hard or soft capsules, or syrups or elixirs. Compositions intended fororal use are prepared according to any method known in the art for themanufacture of pharmaceutical compositions and such compositions cancontain one or more agents selected from the group consisting ofsweetening agents, flavoring agents, coloring agents and preservingagents in order to provide pharmaceutically elegant and palatablepreparations. Tablets contain the active ingredient in admixture withnontoxic pharmaceutically acceptable excipients which are suitable forthe manufacture of tablets. These excipients are, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for example,starch, gelatin or acacia; and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets are uncoated or coated byknown techniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate can be employed. Formulations fororal use can be presented as hard gelatin capsules wherein the activeingredient is mixed with an inert solid diluent, for example, calciumcarbonate, calcium phosphate or kaolin, or as soft gelatin capsuleswherein the active ingredient is mixed with water or an oil medium, forexample, peanut oil, liquid paraffin or olive oil.

Injectable compositions are preferably aqueous isotonic solutions orsuspensions, and suppositories are advantageously prepared from fattyemulsions or suspensions. Said compositions may be sterilized and/orcontain adjuvants, such as preserving, stabilizing, wetting oremulsifying agents, solution promoters, salts for regulating the osmoticpressure and/or buffers. In addition, they may also contain othertherapeutically valuable substances. Said compositions are preparedaccording to conventional mixing, granulating or coating methods,respectively, and contain about 0.1-75%, preferably about 1-50%, of theactive ingredient.

Suitable compositions for transdermal application include an effectiveamount of a compound of the invention with carrier. Advantageouscarriers include absorbable pharmacologically acceptable solvents toassist passage through the skin of the host. For example, transdermaldevices are in the form of a bandage comprising a backing member, areservoir containing the compound optionally with carriers, optionally arate controlling barrier to deliver the compound of the skin of the hostat a controlled and predetermined rate over a prolonged period of time,and means to secure the device to the skin.

Suitable compositions for topical application, e.g., to the skin andeyes, include aqueous solutions, suspensions, ointments, creams, gels orsprayable formulations, e.g., for delivery by aerosol or the like. Suchtopical delivery systems will in particular be appropriate for dermalapplication, e.g., for the treatment of skin cancer, e.g., forprophylactic use in sun creams, lotions, sprays and the like. They arethus particularly suited for use in topical, including cosmetic,formulations well-known in the art. Such may contain solubilizers,stabilizers, tonicity enhancing agents, buffers and preservatives.

The present invention further provides anhydrous pharmaceuticalcompositions and dosage forms comprising the compounds of the presentinvention as active ingredients, since water can facilitate thedegradation of some compounds. For example, the addition of water (e.g.,5%) is widely accepted in the pharmaceutical arts as a means ofsimulating long-term storage in order to determine characteristics suchas shelf-life or the stability of formulations over time. See, e.g.,Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed.,Marcel Dekker, NY, N.Y., 1995, pp. 379-80. In effect, water and heataccelerate the decomposition of some compounds. Thus, the effect ofwater on a formulation can be of great significance since moistureand/or humidity are commonly encountered during manufacture, handling,packaging, storage, shipment, and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms of the inventioncan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. Pharmaceutical compositionsand dosage forms that comprise lactose and at least one activeingredient that comprises a primary or secondary amine are preferablyanhydrous if substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected.

An anhydrous pharmaceutical composition should be prepared and storedsuch that its anhydrous nature is maintained. Accordingly, anhydrouscompositions are preferably packaged using materials known to preventexposure to water such that they can be included in suitable formularykits. Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastics, unit dose containers (e.g., vials),blister packs, and strip packs.

The invention further provides pharmaceutical compositions and dosageforms that comprise one or more agents that reduce the rate by which thecompound of the present invention as an active ingredient willdecompose. Such agents, which are referred to herein as “stabilizers,”include, but are not limited to, antioxidants such as ascorbic acid, pHbuffers, or salt buffers, etc.

The pharmaceutical compositions contain a therapeutically effectiveamount of a compound of the invention as defined above, either alone orin a combination with another therapeutic agent, e.g., each at aneffective therapeutic dose as reported in the art. In one embodiment,such therapeutic agents include, for example, 1) AT₁ receptorantagonists selected from the group consisting of abitesartan,benzyllosartan, candesartan, elisartan, embusartan, enoltasosartan,eprosartan, fonsartan, forasartan, glycyllosartan, irbesartan,isoteoline, losartan, milfasartan, olmesartan, opomisartan, pratosartan,ripisartan, saprisartan, saralasin, sarmesin, tasosartan, telmisartan,valsartan, zolasartan; Kissei KRH-94, Lusofarmaco LR-B/057, LusofarmacoLR-B/081, Lusofarmaco LR B/087, Searle SC-52458, Sankyo CS-866, TakedaTAK-536, Uriach UR-7247, A-81282, A-81988, BIBR-363, BIBS39, BIBS-222,BMS-180560, BMS-184698, CGP-38560A, CGP-48369, CGP-49870, CGP-63170,CI-996, CV-11194, DA-2079, DE-3489, DMP-811, DuP-167, DuP-532, GA-0056,E-4177, EMD-66397, EMD-73495, EXP-063, EXP-929, EXP-3174, EXP-6155,EXP-6803, EXP-7711, EXP-9270, FK-739, HN-65021, HR-720, ICI-D6888,ICI-D7155, ICI-D8731, KR1-1177, KT3-671, KW-3433, L-158809, L-158978,L-159282, L-159689, L-159874, L-161177, L-162154, L-162234, L-162441,L-163007, L-163017, LY-235656, LY-285434, LY-301875, LY-302289,LY-315995, ME-3221, PD-123177, PD-123319, PD-150304, RG-13647,RWJ-38970, RWJ-46458, S-8307, S-8308, SL-91.0102, U-96849, U-97018,UP-269-6, UP-275-22, WAY-126227, WK-1492.2K, WK-1360, X-6803, XH-148,XR-510, YM-358, YM-31472, ZD-6888, ZD-7155 and ZD-8731 which are allknown per se, or any physiologically compatible salts, solvates,prodrugs or esters thereof; 2) non-selective alpha-adrenoceptorantagonists, e.g. tolazoline or phenoxybenzamine; 3) selectivealpha-adrenoceptor antagonists, e.g. doxazosin, prazosin, terazosin orurapidil; beta-adrenoceptor antagonists, e.g. acebutolol, alprenolol,atenolol, betaxolol, bisoprolol, bupranolol, carazolol, carteolol,celiprolol, mepindolol, metipranolol, metoprolol, nadolol, oxprenolol,penbutolol, pindolol, propranolol, sotalol and timolol; 4) mixedantagonists of alpha- and beta-adrenoceptors, e.g. carvedilol orlabetolol; ganglion blockers, e.g. reserpine or guanethidine; 5)alpha2-adrenoceptor agonists (including centrally actingalpha2-adrenoceptor agonists), e.g. clonidine, guanfacine, guanabenzmethyldopa and moxonidine; 6) rennin inhibitors, e.g. alskiren; 7) ACEinhibitors, e.g. benazepril, captopril, cilazapril, enalapril,fosinopril, imidapril, lisinopril, moexipril, quinapril, perindopril,ramipril, spirapril or trandolapril; 8) mixed or selective endothelinreceptor antagonists e.g. atrasentan, bosentan, clazosentan, darusentan,sitaxsentan, tezosentan, BMS-193884 or J-104132; direct vasodilators,e.g. diazoxide, dihydralazine, hydralazine or minoxidil; 9) mixedACE/NEP dual inhibitors, e.g. omapatrilat; ECE inhibitors, e.g.FR-901533; PD-069185; CGS-26303; CGS-34043; CGS-35066; CGS-30084;CGS-35066; SM-19712; Ro0677447; 10) selective NEP inhibitors; 11)vasopressin antagonists; 12) aldosterone receptor antagonists, e.g.eplerenone; 13) aldosterone inhibitors; 14) angiotensin vaccine; 15)urotensin II receptor antagonists; and 16) antiinflamatory agents orantirheumatic agents.

In another embodiment, such therapeutic agents include antiproliferativecompounds. Such antiproliferative compounds include, but are not limitedto aromatase inhibitors; antiestrogens; topoisomerase I inhibitors;topoisomerase II inhibitors; microtubule active compounds; alkylatingcompounds; histone deacetylase inhibitors; compounds which induce celldifferentiation processes; cyclooxygenase inhibitors; MMP inhibitors;mTOR inhibitors; antineoplastic antimetabolites; platin compounds;compounds targeting/decreasing a protein or lipid kinase activity andfurther anti-angiogenic compounds; compounds which target, decrease orinhibit the activity of a protein or lipid phosphatase; gonadorelinagonists; anti-androgens; methionine aminopeptidase inhibitors;bisphosphonates; biological response modifiers; antiproliferativeantibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms;telomerase inhibitors; proteasome inhibitors; compounds used in thetreatment of hematologic malignancies; compounds which target, decreaseor inhibit the activity of Flt-3; Hsp90 inhibitors such as 17-AAG(17-allylaminogeldanamycin, NSC330507), 17-DMAG(17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545),IPI-504, CNF1010, CNF2024, CNF1010 from Conforma Therapeutics;temozolomide (TEMODAL®); kinesin spindle protein inhibitors, such asSB715992 or SB743921 from GlaxoSmithKline, or pentamidine/chlorpromazinefrom CombinatoRx; MEK inhibitors such as ARRY142886 from ArrayPioPharma, AZD6244 from AstraZeneca, PD181461 from Pfizer andleucovorin.

The term “aromatase inhibitor” as used herein relates to a compoundwhich inhibits the estrogen production, i.e. the conversion of thesubstrates androstenedione and testosterone to estrone and estradiol,respectively. The term includes, but is not limited to steroids,especially atamestane, exemestane and formestane and, in particular,non-steroids, especially aminoglutethimide, roglethimide,pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole,fadrozole, anastrozole and letrozole. Exemestane can be administered,e.g., in the form as it is marketed, e.g. under the trademark AROMASIN.Formestane can be administered, e.g., in the form as it is marketed,e.g. under the trademark LENTARON. Fadrozole can be administered, e.g.,in the form as it is marketed, e.g. under the trademark AFEMA.Anastrozole can be administered, e.g., in the form as it is marketed,e.g. under the trademark ARIMIDEX. Letrozole can be administered, e.g.,in the form as it is marketed, e.g. under the trademark FEMARA or FEMAR.Aminoglutethimide can be administered, e.g., in the form as it ismarketed, e.g. under the trademark ORIMETEN. A combination of theinvention comprising a chemotherapeutic agent which is an aromataseinhibitor is particularly useful for the treatment of hormone receptorpositive tumors, e.g. breast tumors.

The term “antiestrogen” as used herein relates to a compound whichantagonizes the effect of estrogens at the estrogen receptor level. Theterm includes, but is not limited to tamoxifen, fulvestrant, raloxifeneand raloxifene hydrochloride. Tamoxifen can be administered, e.g., inthe form as it is marketed, e.g. under the trademark NOLVADEX.Raloxifene hydrochloride can be administered, e.g., in the form as it ismarketed, e.g. under the trademark EVISTA. Fulvestrant can be formulatedas disclosed in U.S. Pat. No. 4,659,516 or it can be administered, e.g.,in the form as it is marketed, e.g. under the trademark FASLODEX. Acombination of the invention comprising a chemotherapeutic agent whichis an antiestrogen is particularly useful for the treatment of estrogenreceptor positive tumors, e.g. breast tumors.

The term “anti-androgen” as used herein relates to any substance whichis capable of inhibiting the biological effects of androgenic hormonesand includes, but is not limited to, bicalutamide (CASODEX), which canbe formulated, e.g. as disclosed in U.S. Pat. No. 4,636,505.

The term “gonadorelin agonist” as used herein includes, but is notlimited to abarelix, goserelin and goserelin acetate. Goserelin isdisclosed in U.S. Pat. No. 4,100,274 and can be administered, e.g., inthe form as it is marketed, e.g. under the trademark ZOLADEX. Abarelixcan be formulated, e.g. as disclosed in U.S. Pat. No. 5,843,901.

The term “topoisomerase I inhibitor” as used herein includes, but is notlimited to topotecan, gimatecan, irinotecan, camptothecian and itsanalogues, 9-nitrocamptothecin and the macromolecular camptothecinconjugate PNU-166148 (compound A1 in WO99/17804). Irinotecan can beadministered, e.g. in the form as it is marketed, e.g. under thetrademark CAMPTOSAR. Topotecan can be administered, e.g., in the form asit is marketed, e.g. under the trademark HYCAMTIN.

The term “topoisomerase II inhibitor” as used herein includes, but isnot limited to the anthracyclines such as doxorubicin (includingliposomal formulation, e.g. CAELYX), daunorubicin, epirubicin,idarubicin and nemorubicin, the anthraquinones mitoxantrone andlosoxantrone, and the podophillotoxines etoposide and teniposide.Etoposide can be administered, e.g. in the form as it is marketed, e.g.under the trademark ETOPOPHOS. Teniposide can be administered, e.g. inthe form as it is marketed, e.g. under the trademark VM 26-BRISTOL.Doxorubicin can be administered, e.g. in the form as it is marketed,e.g. under the trademark ADRIBLASTIN or ADRIAMYCIN. Epirubicin can beadministered, e.g. in the form as it is marketed, e.g. under thetrademark FARMORUBICIN. Idarubicin can be administered, e.g. in the formas it is marketed, e.g. under the trademark ZAVEDOS. Mitoxantrone can beadministered, e.g. in the form as it is marketed, e.g. under thetrademark NOVANTRON.

The term “microtubule active agent” relates to microtubule stabilizing,microtubule destabilizing compounds and microtublin polymerizationinhibitors including, but not limited to taxanes, e.g. paclitaxel anddocetaxel, vinca alkaloids, e.g., vinblastine, especially vinblastinesulfate, vincristine especially vincristine sulfate, and vinorelbine,discodermolides, cochicine and epothilones and derivatives thereof, e.g.epothilone B or D or derivatives thereof. Paclitaxel may be administerede.g. in the form as it is marketed, e.g. TAXOL. Docetaxel can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark TAXOTERE. Vinblastine sulfate can be administered, e.g., inthe form as it is marketed, e.g. under the trademark VINBLASTIN R.P.Vincristine sulfate can be administered, e.g., in the form as it ismarketed, e.g. under the trademark FARMISTIN. Discodermolide can beobtained, e.g., as disclosed in U.S. Pat. No. 5,010,099. Also includedare Epothilone derivatives which are disclosed in WO 98/10121, U.S. Pat.No. 6,194,181, WO 98/25929, WO 98/08849, WO 99/43653, WO 98/22461 and WO00/31247. Especially preferred are Epothilone A and/or B.

The term “alkylating agent” as used herein includes, but is not limitedto, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU orGliadel). Cyclophosphamide can be administered, e.g., in the form as itis marketed, e.g. under the trademark CYCLOSTIN. Ifosfamide can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark HOLOXAN.

The term “histone deacetylase inhibitors” or “HDAC inhibitors” relatesto compounds which inhibit the histone deacetylase and which possessantiproliferative activity. This includes compounds disclosed in WO02/22577, especiallyN-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide,N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamideand pharmaceutically acceptable salts thereof. It further especiallyincludes Suberoylanilide hydroxamic acid (SAHA).

The term “antineoplastic antimetabolite” includes, but is not limitedto, 5-Fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylatingcompounds, such as 5-azacytidine and decitabine, methotrexate andedatrexate, and folic acid antagonists such as pemetrexed. Capecitabinecan be administered, e.g., in the form as it is marketed, e.g. under thetrademark XELODA. Gemcitabine can be administered, e.g., in the form asit is marketed, e.g. under the trademark GEMZAR.

The term “platin compound” as used herein includes, but is not limitedto, carboplatin, cis-platin, cisplatinum and oxaliplatin. Carboplatincan be administered, e.g., in the form as it is marketed, e.g. under thetrademark CARBOPLAT. Oxaliplatin can be administered, e.g., in the formas it is marketed, e.g. under the trademark ELOXATIN.

The term “compounds targeting/decreasing a protein or lipid kinaseactivity; or a protein or lipid phosphatase activity; or furtheranti-angiogenic compounds” as used herein includes, but is not limitedto, protein tyrosine kinase and/or serine and/or threonine kinaseinhibitors or lipid kinase inhibitors, e.g.,

a) compounds targeting, decreasing or inhibiting the activity of theplatelet-derived growth factor-receptors (PDGFR), such as compoundswhich target, decrease or inhibit the activity of PDGFR, especiallycompounds which inhibit the PDGF receptor, e.g. aN-phenyl-2-pyrimidine-amine derivative, e.g. imatinib, SU101, SU6668 andGFB-111;

b) compounds targeting, decreasing or inhibiting the activity of thefibroblast growth factor-receptors (FGFR);

c) compounds targeting, decreasing or inhibiting the activity of theinsulin-like growth factor receptor I (IGF-IR), such as compounds whichtarget, decrease or inhibit the activity of IGF-IR, especially compoundswhich inhibit the kinase activity of IGF-I receptor, such as thosecompounds disclosed in WO 02/092599, or antibodies that target theextracellular domain of IGF-I receptor or its growth factors;

d) compounds targeting, decreasing or inhibiting the activity of the Trkreceptor tyrosine kinase family, or ephrin B4 inhibitors;

e) compounds targeting, decreasing or inhibiting the activity of the Axlreceptor tyrosine kinase family;

f) compounds targeting, decreasing or inhibiting the activity of the Retreceptor tyrosine kinase;

g) compounds targeting, decreasing or inhibiting the activity of theKit/SCFR receptor tyrosine kinase, e.g. imatinib;

h) compounds targeting, decreasing or inhibiting the activity of theC-kit receptor tyrosine kinases—(part of the PDGFR family), such ascompounds which target, decrease or inhibit the activity of the c-Kitreceptor tyrosine kinase family, especially compounds which inhibit thec-Kit receptor, e.g. imatinib;

i) compounds targeting, decreasing or inhibiting the activity of membersof the c-Abl family, their gene-fusion products (e.g. BCR-Abl kinase)and mutants, such as compounds which target decrease or inhibit theactivity of c-Abl family members and their gene fusion products, e.g. aN-phenyl-2-pyrimidine-amine derivative, e.g. imatinib or nilotinib(AMN107); PD180970; AG957; NSC 680410; PD173955 from ParkeDavis; ordasatinib (BMS-354825)

j) compounds targeting, decreasing or inhibiting the activity of membersof the protein kinase C (PKC) and Raf family of serine/threoninekinases, members of the MEK, SRC, JAK, FAK, PDK1, PKB/Akt, and Ras/MAPKfamily members, and/or members of the cyclin-dependent kinase family(CDK) and are especially those staurosporine derivatives disclosed inU.S. Pat. No. 5,093,330, e.g. midostaurin; examples of further compoundsinclude e.g. UCN-01, safingol, BAY 43-9006, Bryostatin 1, Perifosine;Ilmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521;LY333531/LY379196; isochinoline compounds such as those disclosed in WO00/09495; FTIs; PD184352 or QAN697 (a PI3K inhibitor) or AT7519 (CDKinhibitor);

k) compounds targeting, decreasing or inhibiting the activity ofprotein-tyrosine kinase inhibitors, such as compounds which target,decrease or inhibit the activity of protein-tyrosine kinase inhibitorsinclude imatinib mesylate (GLEEVEC) or tyrphostin. A tyrphostin ispreferably a low molecular weight (Mr<1500) compound, or apharmaceutically acceptable salt thereof, especially a compound selectedfrom the benzylidenemalonitrile class or the 5-arylbenzenemalonirile orbisubstrate quinoline class of compounds, more especially any compoundselected from the group consisting of Tyrphostin A23/RG-50810; AG 99;Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; TyrphostinB44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494;Tyrphostin AG 556, AG957 and adaphostin(4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester;NSC 680410, adaphostin);

l) compounds targeting, decreasing or inhibiting the activity of theepidermal growth factor family of receptor tyrosine kinases (EGFR,ErbB2, ErbB3, ErbB4 as homo- or heterodimers) and their mutants, such ascompounds which target, decrease or inhibit the activity of theepidermal growth factor receptor family are especially compounds,proteins or antibodies which inhibit members of the EGF receptortyrosine kinase family, e.g. EGF receptor, ErbB2, ErbB3 and ErbB4 orbind to EGF or EGF related ligands, and are in particular thosecompounds, proteins or monoclonal antibodies generically andspecifically disclosed in WO 97/02266, e.g. the compound of ex. 39, orin EP 0 564 409, WO 99/03854, EP 0520722, EP 0 566 226, EP 0 787 722, EP0 837 063, U.S. Pat. No. 5,747,498, WO 98/10767, WO 97/30034, WO97/49688, WO 97/38983 and, especially, WO 96/30347 (e.g. compound knownas CP 358774), WO 96/33980 (e.g. compound ZD 1839) and WO 95/03283 (e.g.compound ZM105180); e.g. trastuzumab (Herceptin™), cetuximab (Erbitux™),Iressa, Tarceva, OSI-774, CI-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5,E6.2, E6.4, E2.11, E6.3 or E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidinederivatives which are disclosed in WO 03/013541; and

m) compounds targeting, decreasing or inhibiting the activity of thec-Met receptor, such as compounds which target, decrease or inhibit theactivity of c-Met, especially compounds which inhibit the kinaseactivity of c-Met receptor, or antibodies that target the extracellulardomain of c-Met or bind to HGF.

Further anti-angiogenic compounds include compounds having anothermechanism for their activity, e.g. unrelated to protein or lipid kinaseinhibition e.g. thalidomide (THALOMID) and TNP-470.

Compounds which target, decrease or inhibit the activity of a protein orlipid phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A,or CDC25, e.g. okadaic acid or a derivative thereof.

Compounds which induce cell differentiation processes are e.g. retinoicacid, α- γ- or δ-tocopherol or α- γ- or δ-tocotrienol.

The term cyclooxygenase inhibitor as used herein includes, but is notlimited to, e.g. Cox-2 inhibitors, 5-alkyl substituted2-arylaminophenylacetic acid and derivatives, such as celecoxib(CELEBREX), rofecoxib (VIOXX), etoricoxib, valdecoxib or a5-alkyl-2-arylaminophenylacetic acid, e.g.5-methyl-2-(2′-chloro-6′-fluoroanilino)phenyl acetic acid, lumiracoxib.

The term “bisphosphonates” as used herein includes, but is not limitedto, etridonic, clodronic, tiludronic, pamidronic, alendronic,ibandronic, risedronic and zoledronic acid. “Etridonic acid” can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark DIDRONEL. “Clodronic acid” can be administered, e.g., in theform as it is marketed, e.g. under the trademark BONEFOS. “Tiludronicacid” can be administered, e.g., in the form as it is marketed, e.g.under the trademark SKELID. “Pamidronic acid” can be administered, e.g.in the form as it is marketed, e.g. under the trademark AREDIA™.“Alendronic acid” can be administered, e.g., in the form as it ismarketed, e.g. under the trademark FOSAMAX. “Ibandronic acid” can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark BONDRANAT. “Risedronic acid” can be administered, e.g., in theform as it is marketed, e.g. under the trademark ACTONEL. “Zoledronicacid” can be administered, e.g. in the form as it is marketed, e.g.under the trademark ZOMETA.

The term “mTOR inhibitors” relates to compounds which inhibit themammalian target of rapamycin (mTOR) and which possess antiproliferativeactivity such as sirolimus (Rapamune®), everolimus (Certican™), CCI-779and ABT578.

The term “heparanase inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit heparin sulfate degradation. The termincludes, but is not limited to, PI-88.

The term “biological response modifier” as used herein refers to alymphokine or interferons, e.g. interferon γ.

The term “inhibitor of Ras oncogenic isoforms”, e.g. H-Ras, K-Ras, orN-Ras, as used herein refers to compounds which target, decrease orinhibit the oncogenic activity of Ras e.g. a “farnesyl transferaseinhibitor” e.g. L-744832, DK8G557 or R115777 (Zarnestra).

The term “telomerase inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit the activity of telomerase. Compounds whichtarget, decrease or inhibit the activity of telomerase are especiallycompounds which inhibit the telomerase receptor, e.g. telomestatin.

The term “methionine aminopeptidase inhibitor” as used herein refers tocompounds which target, decrease or inhibit the activity of methionineaminopeptidase. Compounds which target, decrease or inhibit the activityof methionine aminopeptidase are e.g. bengamide or a derivative thereof.

The term “proteasome inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit the activity of the proteasome. Compoundswhich target, decrease or inhibit the activity of the proteasome includee.g. Bortezomid (Velcade™) and MLN 341.

The term “matrix metalloproteinase inhibitor” or (“MMP” inhibitor) asused herein includes, but is not limited to, collagen peptidomimetic andnonpeptidomimetic inhibitors, tetracycline derivatives, e.g. hydroxamatepeptidomimetic inhibitor batimastat and its orally bioavailable analoguemarimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551)BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.

The term “compounds used in the treatment of hematologic malignancies”as used herein includes, but is not limited to, FMS-like tyrosine kinaseinhibitors e.g. compounds targeting, decreasing or inhibiting theactivity of FMS-like tyrosine kinase receptors (Flt-3R); interferon,1-b-D-arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitorse.g. compounds which target, decrease or inhibit anaplastic lymphomakinase.

Compounds which target, decrease or inhibit the activity of FMS-liketyrosine kinase receptors (Flt-3R) are especially compounds, proteins orantibodies which inhibit members of the Flt-3R receptor kinase family,e.g. PKC412, midostaurin, a staurosporine derivative, SU11248 andMLN518.

The term “HSP90 inhibitors” as used herein includes, but is not limitedto, compounds targeting, decreasing or inhibiting the intrinsic ATPaseactivity of HSP90; degrading, targeting, decreasing or inhibiting theHSP90 client proteins via the ubiquitin proteosome pathway. Compoundstargeting, decreasing or inhibiting the intrinsic ATPase activity ofHSP90 are especially compounds, proteins or antibodies which inhibit theATPase activity of HSP90 e.g., 17-allylamino,17-demethoxygeldanamycin(17AAG), a geldanamycin derivative; other geldanamycin relatedcompounds; radicicol and HDAC inhibitors.

The term “antiproliferative antibodies” as used herein includes, but isnot limited to, trastuzumab (Herceptin™), Trastuzumab-DM1, erbitux,bevacizumab (Avastin™), rituximab (Rituxan®), PRO64553 (anti-CD40) and2C4 Antibody. By antibodies is meant e.g. intact monoclonal antibodies,polyclonal antibodies, multispecific antibodies formed from at least 2intact antibodies, and antibodies fragments so long as they exhibit thedesired biological activity.

Furthermore, the combinations as described above can be administered toa subject via simultaneous, separate or sequential administration (use).Simultaneous administration (use) can take place in the form of onefixed combination with two or more active ingredients, or bysimultaneously administering two or more compounds that are formulatedindependently. Sequential administration (use) preferably meansadministration of one (or more) compounds or active ingredients of acombination at one time point, other compounds or active ingredients ata different time point, that is, in a chronically staggered manner,preferably such that the combination shows more efficiency than thesingle compounds administered independently (especially showingsynergism). Separate administration (use) preferably meansadministration of the compounds or active ingredients of the combinationindependently of each other at different time points, preferably meaningthat two compounds are administered such that no overlap of measurableblood levels of both compounds are present in an overlapping manner (atthe same time).

Also combinations of two or more of sequential, separate andsimultaneous administrations are possible, preferably such that thecombination compound-drugs show a joint therapeutic effect that exceedsthe effect found when the combination compound-drugs are usedindependently at time intervals so large that no mutual effect on theirtherapeutic efficiency can be found, a synergistic effect beingespecially preferred.

Additionally, the present invention provides:

-   -   a pharmaceutical composition or combination of the present        invention for use as a medicament;    -   the use of a pharmaceutical composition or combination of the        present invention for the delay of progression and/or treatment        of a disorder or disease mediated by MMP-2, and/or MMP-8, and/or        MMP-9, and/or MMP-12 and/or MMP-13.    -   the use of a pharmaceutical composition or combination of the        present invention for the delay of progression and/or treatment        of a disorder or disease selected from hypokalemia,        hypertension, congestive heart failure, renal failure, in        particular, chronic renal failure, restenosis, atherosclerosis,        syndrome X, obesity, nephropathy, post-myocardial infarction,        coronary heart diseases, increased formation of collagen,        fibrosis and remodeling following hypertension and endothelial        dysfunction.    -   the use of a pharmaceutical composition or combination of the        present invention for the delay of progression and/or treatment        of a disorder or disease selected from gynecomastia,        osteoporosis, prostate cancer, endometriosis, uterine fibroids,        dysfunctional uterine bleeding, endometrial hyperplasia,        polycystic ovarian disease, infertility, fibrocystic breast        disease, breast cancer and fibrocystic mastopathy.

The pharmaceutical composition or combination of the present inventioncan be in unit dosage of about 1-1000 mg of active ingredients for asubject of about 50-70 kg, preferably about 5-500 mg of activeingredients. The therapeutically effective dosage of a compound, thepharmaceutical composition, or the combinations thereof, is dependent onthe species of the subject, the body weight, age and individualcondition, the disorder or disease or the severity thereof beingtreated. A physician, clinician or veterinarian of ordinary skill canreadily determine the effective amount of each of the active ingredientsnecessary to prevent, treat or inhibit the progress of the disorder ordisease.

The above-cited dosage properties are demonstrable in vitro and in vivotests using advantageously mammals, e.g., mice, rats, dogs, monkeys orisolated organs, tissues and preparations thereof. The compounds of thepresent invention can be applied in vitro in the form of solutions,e.g., preferably aqueous solutions, and in vivo either enterally,parenterally, advantageously intravenously, e.g., as a suspension or inaqueous solution. The dosage in vitro may range between about 10⁻³ molarand 10⁻⁹ molar concentrations. A therapeutically effective amount invivo may range depending on the route of administration, between about0.1-500 mg/kg, preferably between about 1-100 mg/kg.

The compounds are particularly useful for the treatment of, for example,inflammatory conditions, osteoarthritis, rheumatoid arthritis andtumors. Beneficial effects are evaluated in pharmacological testsgenerally known in the art, and as illustrated herein.

Antiinflammatory activity can be determined in standard inflammation andarthritic animal models well-known in the art, e.g. the adjuvantarthritis model in rats and the collagen II induced arthritis model inmice (Mediators of Inflam. 1, 273-279 (1992).

Gelatinase (MMP-2) inhibitory activities can be determined as follows:Stock solutions of substrate (MCA-Lys-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH₂)are prepared in DMSO at a concentration of 1.4 mM. Stock solutions ofinhibitors (0.03 μM-3 mM) are also prepared in DMSO. The inhibitors arediluted into the assay solutions, and the controls use an equal volumeof DMSO so that the final DMSO concentration from the inhibitor andsubstrate dilutions in all assays is 1.0%. Assays are performed in anassay buffer (100 mM sodium chloride, 10 μM ZnCl. Sub 2, 10 mMCaCl.sub.2, 100 mM Tris-Cl pH7.5, 0.05% Brij-35), containing 1.0% DMSOfrom the substrate and inhibitor additions. The substrate concentrationused in the assays is 5 μM. The assays are carried out at 20-25° C. Thefluorescence changes, as a result of substrate cleavage, are monitoredusing an excitation wavelength of 325 nm and an emission wavelength of405 nm. The reaction mixtures are added in duplicate into appropriatewells of a 384-well assay plate. The reaction mixtures are preincubatedwith the inhibitors for 60 minutes. The reactions are started by theaddition of MMP substrate, and the fluorescence intensity changes aremeasured after 60 minutes. The apparent enzyme activity in the presenceof an inhibitor is then compared with that in the absence of anyinhibitor to determine the inhibition effect of the inhibitor. Thesetechniques are within the knowledge of one skilled in the art. Theinhibition results are expressed as the inhibitor concentrationsrequired to effect 50% inhibition (IC₅₀) of the enzyme activity, ascompared with the control (non-inhibited) reactions.

Illustrative of the invention, compound 80 in the Tables below exhibitsan IC₅₀ of 55 nM.

Collagenase-3 (MMP-13) inhibitory activity is determined as describedabove. Recombinant pro-collagenase-3 is activated with 1 mM APMA, andstored in the assay buffer after extensive dialysis in the assay buffer.

Illustrative of the invention, compound 80 in the Tables below exhibitsan IC₅₀ of about 113 nM.

MMP-12 inhibitory activity is determined as described above.

The effect of compounds of the invention in vivo can be determined inrats. Typically, six rats are dosed orally with a compound up to fourhours before being injected intra-articularly in both knees (N=12) with0.1 to 2 ug/knee of recombinant human MMP-13 dissolved 0.05 mL ofsaline. Two hours later the rats are sacrificed, synovial lavage iscollected, and chondroitin sulfate (CS) fragments released into thejoint are quantitated. Chondroitin sulfate is measured by an inhibitionELISA using a chondrotin sulfate specific antibody (CS-56—available fromSigma), in an analogous manner to the methods described by Thonar(Thonar, E. J.-M. A., Lenz, M. E., Klinsworth, G. K., Caterson, B.,Pachman, L. M., Glickman, P., Katz, R., Huff, J., Keuttner, K. E.Quantitation of keratan sulfate in blood as a marker of cartilagecatabolism, Arth. Rheum. 28, 1367-1376 (1985)).

The effect in protecting against cartilage degradation in arthriticdisorders can be determined e.g. in a surgical model of osteoarthritisdescribed in Arthritis and Rheumatism, Vol. 26, 875-886 (1983).

The effect of the compounds of the invention for the treatment ofemphysema can be determined in animal models described in AmericanReview of Respiratory Disease 117, 1109 (1978).

The antitumor effect of the compounds of the invention can bedetermined, for example, by measuring the growth of human tumorsimplanted subcutaneously in Balb/c nude mice according to methodologywell-known in the art in comparison to placebo treated mice.Illustrative tumors are, for example, estrogen-dependent human breastcarcinoma BT20 and MCF7, human bladder carcinoma T24, human coloncarcinoma Colo 205, human lung adenocarcinoma A549, and human ovariancarcinoma NIH-OVCAR3.

The inhibition of tumor metastasis can be determined in two lungmetastasis models. In the B16-F10 melanoma model, metastasis is measuredby counting the numbers of lung metastasized melanoma nodules producedby intravenously injected B16-F10 melanoma cells into BDF1 treated mice,according to methodology well known in the art. In the HT1080 model,metastasis is quantified by measuring the fluorescence intensity ofenhanced green fluorescent protein (EGFP) in the lung of Balb/c nudemice produced by the metastasized tumor from intravenously injectedGFP-expressing human fibrosarcoma HT1080 cells. The inhibition isobtained by comparison of compound-treated and placebo-treated mice inboth methods. In the HT1080 model, EGFP-expressing HT1080 cells areprepared by limiting dilution method in the presence of geneticin aftertransfecting the EGFP expression vector (pEGFP-Cl) (CLONTECHLaboratories Inc., Palo Alto, Calif.). A suspension of cells (10⁶cells/0.1 mL of PBS) is injected intravenously into Balb/c nude mice.After administering test compounds and vehicle p.o. 3 weeks, tumormetastasized lungs of mice are removed after sacrifice and homogenized.After centrifugation, the cells are washed 3 times with lysing reagent(150 mM ammonium chloride, 0.1 mM EDTA-4 Na, 10 mM KHCO₃, pH 7.4) tolyse the red blood cells and 2 times with PBS. After centrifugation,EGFP is extracted from cells by 10% Triton in PBS and put into the wellsof a 96-well multi plate. The fluorescence intensity is determined usinga fluorescence plate reader at the excitation and emission wave lengthsof 485 and 530 nm, respectively.

The effect of the compounds of the invention on atheroscleroticconditions can be evaluated using atherosclerotic plaques fromcholesterol-fed rabbits which contain activated matrixmetalloproteinases as described by Sukhova et al, Circulation 90, 1404(1994). The inhibitory effect on matrix metalloproteinase enzymeactivity in rabbit atherosclerotic plaques can be determined by in situzymography, as described by Galis et al, J. Clin. Invest. 94, 2493(1994), and is indicative of plaque rupture.

The compounds of the invention are particularly useful in mammals asantiinflammatory agents for the treatment of, for example,osteoarthritis and rheumatoid arthritis, as antitumor agents for thetreatment and prevention of tumors growth, tumor metastasis, tumorinvasion or progression, and as antiatherosclerotic agents for thetreatment and prevention of the rupture of atherosclerotic plaques.

The present invention also relates to methods of using the compounds ofthe invention and their pharmaceutically acceptable salts, orpharmaceutical compositions thereof, in mammals for inhibiting thematrix-degrading metalloproteinases, e.g. stromelysin, gelatinase,collagenase and macrophage metalloelastase, for inhibiting tissue matrixdegradation, and for the treatment of matrix-degrading metalloproteinasedependent conditions as described herein, e.g. inflammation, rheumatoidarthritis, osteoarthritis, also tumors (tumor growth, metastasis,progression or invasion), pulmonary disorders, and the like describedherein. Tumors (carcinomas) include mammalian breast, lung, bladder,colon, prostate and ovarian cancer, and skin cancer, including melanomaand Kaposi's sarcoma.

The following Examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees Centrigrade. If not mentioned otherwise, all evaporations areperformed under reduced pressure, preferably between about 15 and 100mmHg (20-133 mbar). The structures of final products, intermediates andstarting materials are confirmed by standard analytical methods, e.g.microanalysis and/or spectroscopic characteristics (e.g. MS, IR, orNMR). Abbreviations used are those conventional in the art.

EXAMPLES

The present invention will now be illustrated by reference to thefollowing examples which set forth particularly advantageousembodiments. However, it should be noted that these embodiments areillustrative and are not to be construed as restricting the invention inany way.

Example 1 3-(4-Methoxy-benzoyl)-benzenesulfonamide

3-(4-Methoxy-benzoyl)-benzenesulfonyl chloride

Under a nitrogen atmosphere, aluminum chloride (7.5 g, 56.5 mmol) isslurried in dichloromethane (150 mL) then 3-chlorosulfonyl-benzoylchloride (7.5 g, 31.4 mmol) is added and allowed to stir at ambienttemperature for 10 minutes. Anisole (4.06 g, 37.65 mmol) is added. Thereaction is allowed to stir at ambient temperature for 18 hours. Thereaction mixture is poured over ice-cold 6 N HCl and extracted withdichloromethane to give a purple oil. Purification by silica gelchromatography (10% ethyl acetate in hexanes) yielded 4 g (41% yield) ofthe title compound as a yellow powder. ¹H NMR (CDCl₃): δ 8.5 (t, 1H,J=1.7 Hz), 8.25 (m, 1H), 8.1 (m, 1H), 7.7-7.9 (m, 3H), 7.0 (d, 2H, J=6.9Hz), 3.9 (s, 3H).

3-(4-Methoxy-benzoyl)benzenesulfonamide

3-(4-Methoxy-benzoyl)-benzenesulfonyl chloride is dissolved indichloromethane (10 ml) and treated with 1.7 mL of a 2 M solution ofammonia in methanol. The reaction is stirred at ambient temperature for2 hours and quenched with 1N HCl. The organic phase is separated andevaporated under reduced pressure to give the crude sulfonamide.Purification by silica gel chromatography (gradient of ethyl acetate inhexanes 5-25%) yielded 100 mg (50% yield) of the title compound. ¹H NMR(CDCl₃, 300 MHz): δ 8.3 (t, 1H, J=1.6 Hz), 8.1 (m, 1H), 7.95 (m, 1H),7.8 (d, 2H, J=6.98 Hz), 7.65 (t, 1H, J=7.8 Hz), 7.0 (d, 2H, J=6.98 Hz),4.95 (s, 2H), 3.9 (s, 3H). MP: 119-122° C. LCMS Elution time 0.81 MS(m/z): 291 (M+1). CHN Calc C, 57.72; H, 4.50; N, 4.81. Found C, 57.65;H, 4.33; N, 4.69

Example 2 2-fluoro-5-(4-methoxy-benzoyl)-benzenesulfonamide3-Chlorosulfonyl-4-fluoro benzoic acid

4-Fluoro-benzoic acid (8 g, 57 mmol) is added carefully tochlorosulfonic acid (58 g, 498 mmol) then sodium chloride (10 g, 169mmol) is added in small portions. After complete addition, the reactionis heated at 160° C. for 5 h. The reaction mixture is cooled down andpoured into ice-water. A white solid precipitate is collected andredissolved in ethyl acetate. The organic layer is washed with asaturated sodium chloride solution, dried over magnesium sulfate,filtered, and the solvent is removed in vacuo. The residue is trituratedwith hexane to give 7 g (51% yield) of the title compound as a whitesolid. ¹H NMR (CDCl₃): δ 8.78 (m, 1H), 8.52 (m, 1H), 7.5 (t, 1H). MS(m/z): 308 (M−1).

3-Chlorosulfonyl-4-fluoro benzoyl chloride

To a suspension of 3-chlorosulfonyl-4-fluoro benzoic acid (2.5 g, 10mmol) in methylene chloride at 0° C. is added oxalyl chloride (1.33 g,11 mmol), followed by the addition of 1 drop of N,N,-dimethylformamide.The reaction mixture is warmed up to room temperature and stirred for anadditional 4 h. The solvent is removed, and the residue is dried undervacuum for 1 hr to obtain the title compound as an oil, which is usedfor the next step without further purification.

2-Fluoro-5-(4-methoxy-benzoyl)-benzenesulfonyl chloride

To a suspension of aluminium chloride (2.1 g, 15.7 mmol) in methylenechloride (50 mL) is added 3-chlorosulfonyl-4-fluoro benzoyl chloride(10.5 mmol). The reaction mixture is stirred at room temperature for 10minutes then anisole (1.36 g, 12.5 mmol) is added. After the mixture isstirred at room temperature for 16 h, the reaction is quenched with 6 NHCl, and extracted with methylene chloride three times. The combinedorganic layers are washed with a saturated sodium chloride solution,dried with magnesium sulfate, and concentrated in vacuo. Purification bysilica gel chromatography (ethyl acetate/hexane: 1:9) followed byrecrystallization (methylene chloride-hexane) provides 1.8 g (54% yield)of the title compound as a white solid. ¹H NMR (CDCl₃): δ 8.41 (m, 1H),8.20 (m, 1H), 7.82 (d, J=15 Hz, 2H), 7.50 (t, 1H), 7.08 (d, J=15 Hz,2H), 3.95 (s, 3H).

2-Fluoro-5-(4-methoxy-benzoyl)-benzenesulfonamide

To a solution of 2-fluoro-5-(4-methoxy-benzoyl)-benzenesulfonyl chloride(0.45 g, 1.0 mmol) in methylene chloride is added aqueous ammoniumsolution (1 mL). The reaction mixture is stirred for 10 min at roomtemperature. The solvent is removed and the residue is redissolved inethyl acetate and extracted with water. The organic layers are washedwith a saturated sodium chloride solution, dried with magnesium sulfate,and concentrated in vacuo. The residue is recrystallized with methylenechloride-hexane to give 100 mg (32% yield) of the title compound as paleyellow solid. ¹H NMR (CDCl₃): δ 8.40 (m, 1H), 8.05 (m, 1H), 7.80 (d, J=8Hz, 2H), 7.32 (t, 1H), 7.00 (d, J=8 Hz, 2H), 5.15 (s, 1H), 3.90 (s, 3H).Analytics calculated for C₁₄H₁₂FNO₄S: C, 54.36; H, 3.91; N, 4.53. Found:C, 53.89; H, 3.50; N, 4.50.

Example 3 2-Chloro-5-(4-methoxy-benzoyl)-benzenesulfonamide

2-Chloro-5-(4-methoxy-benzoyl)-benzenesulfonamide

Under nitrogen, aluminum chloride (1.95 g, 14.6 mmol) is slurried indichloromethane (50 mL) then 4-chloro-3-sulfamoyl benzoyl chloride isadded and allowed to stir at ambient temperature for 30 minutes. Anisole(683 mg, 6.3 mmol) is added in 2 mL methylene chloride. The reaction isallowed to stir at ambient temperature for 18 hours. The reactionmixture is poured over ice-cold 6 N HCl and extracted withdichloromethane to give a colorless oil. Purification by silica gelchromatography (gradient of ethyl acetate in hexanes 5-25%) yielded awhite foam which is crystallized three times from ether to afford thetitle compound. ¹H NMR (MeOD) δ 3.9 (s, 3H), 7.1 (d, 2H, J=8.84 Hz),7.7-8.0 (m, 4H), 8.4 (d, 1H, J=1.96 Hz). MS (m/z): 326 (M+1). CHN CalcC, 51.62; H, 3.71; N, 4.3. Found C, 51.70; H, 3.76; N 4.22. M.P.156-158° C.

Example 4 2,3-Difluoro-5-(4-methoxy-benzoyl)-benzenesulfonamide

2,3-Difluoro-5-(4-methoxy-benzoyl)-benzenesulfonamide is prepared asdescribed above for 2-fluoro-5-(4-methoxy-benzoyl)-benzenesulfonamide.¹H NMR (CDCl₃): δ 8.0 (m, 1H), 7.88 (m, 1H), 7.80 (d, J=15 Hz, 2H), 7.00(d, J=15 Hz, 2H), 5.30 (s, 2H), 3.92 (s, 3H). Analytics calculated forC₁₄H₁₁F₂NO₄S: C, 51.38; H, 3.39; N, 4.28. Found: C, 51.98; H, 3.76; N,3.86. MS (m/z): 326 (M−1).

Example 5 5-(4-Methoxy-benzoyl)-2-nitro-benzenesulfonamide

2-Amino-5-(4-methoxy-benzoyl)-benzenesulfinamide

To a solution of 2-fluoro-5-(4-methoxy-benzoyl)-benzenesulfonamide (0.25g, 0.81 mmol) dissolved in dioxane (3 mL) is added aqueous ammoniasolution (1 mL). The reaction mixture is heated at 100° C. for 6 h insealed tube and then cooled to room temperature and concentrated invacuo. The residue is partitioned between water and ethyl acetate, andthe aqueous phase is extracted with ethyl acetate three times. Thecombined organic extracts are washed with a saturated sodium chloridesolution, dried with magnesium sulfate, and concentrated in vacuo toprovide 0.2 g (81%) of the title compound as a pale yellow solid. ¹H NMR(DMSO): δ 8.05 (d, J=2 Hz, 1H), 7.70 (m, 3H), 7.40 (s, 2H), 7.05 (d, J=9Hz, 2H), 6.92 (d, J=9 Hz, 1H), 3.88 (s, 3H).

5-(4-Methoxy-benzoyl)-2-nitro-benzenesulfonamide

To a solution of 2-amino-5-(4-methoxy-benzoyl)-benzenesulfinamide (0.15g, 0.49 mmol) dissolved in acetic acid (2 mL) is added NaBO₃.water(0.215 g, 2.16 mmol). The reaction mixture is heated at 50° C. for 7 hand then cooled to room temperature. Sodium hydroxide (solid) is addedto neutralize the mixture, and the solution is then extracted withmethylene chloride three times. The combined organic extracts are washedwith a saturated sodium chloride solution, dried with magnesium sulfate,and concentrated in vacuo. The resulting residue is dissolved indioxane, followed by the addition of 1 N of sodium hydroxide solution (2mL). After stirring at 50° C. for 1 h, the mixture is cooled to roomtemperature and concentrated in vacuo. The residue is partitionedbetween water and methylene chloride, and the aqueous phase is extractedwith methylene chloride three times. The combined organic extracts arewashed with a saturated sodium chloride solution, dried with magnesiumsulfate, and concentrated in vacuo. Purification by silica gelchromatography (50% ethyl acetate-hexane) followed by recrystallization(methylene chloride-hexane) provides 0.038 g (28%) of the title compoundas a pale yellow solid. ¹H NMR (CDCl₃): δ 8.50 (d, J=1 Hz, 1H), 8.05 (m,2H), 7.80 (d, J=8 Hz, 2H), 7.00 (d, J=8 Hz, 2H), 5.50 (s, 1H), 3.90 (s,3H). Analytics calculated for C₁₄H₁₂N₂O₆S: C, 50.00; H, 3.60; N, 8.33.Found: C, 49.99; H, 3.41; N, 7.96. MS (m/z): 335 (M−1).

Example 6 5-(4-Methoxy-benzoyl)-2-methyl-benzenesulfonamide

3-Chlorosulfonyl-4-methyl-benzoic acid

Sodium chloride (8 g, 138 mmol) is added to chlorosulfonic acid (30 mL,451 mmol) and in small portions 4-methyl-benzoic acid (4 g, 29 mmol) isadded to the stirred mixture. After complete addition, the reaction isheated at 122° C. for 16 h. The reaction mixture is cooled and pouredinto ice-water. The organic material is extracted with ethyl acetate.The organic layer is washed with a saturated sodium chloride solution,dried over magnesium sulfate, filtered, and the solvent is removed invacuo. The residue is used as is in the next step.

4-Methyl-3-sulfamoyl-benzoic acid

A solution of ammonia in methanol (40 mL, 2 M) is added to the crude3-chlorosulfonyl-4-methyl-benzoic acid and the solution stirred at roomtemperature for 16 hours. The volume is reduced by 50% by heating underreduced pressure, the solution is filtered to remove the precipitate andthe precipitate washed with additional methanol. The sulphonamideprecipitate is used directly in the next step.

4-methyl-3-sulfamoyl-benzoyl chloride

4-Methyl-3-sulfamoyl-benzoic acid (2 g, 10 mmol) is added to thionylchloride (15 mL) and heated at reflux for 3 hours. Hexanes are added tothe cooled solution and an oil forms. The hexanes are decanted and theoil is dissolved in methylene chloride and washed with hexanes. Thesolvent is removed under reduced pressure and the crude oil used in thenext step.

5-(4-Methoxy-benzoyl)-2-methyl-benzenesulfonamide

To a suspension of aluminium chloride (906 mg, 6.8 mmol) in methylenechloride (20 mL) is added 4-methyl-3-sulfamoyl-benzoyl chloride (1.1 g,4.7 mmol) and anisole (1.1 g, 10.2 mmol). After the mixture is stirredat room temperature for 16 h, the reaction is quenched with 6 N HCl, andextracted with methylene chloride three times. The combined organiclayers are washed with a saturated sodium chloride solution, dried withmagnesium sulfate, and concentrated in vacuo. On standing, crystals formand trituration with diethyl ether and ethyl acetate provides 0.84 g(58% yield) of the title compound as a white solid. MS (m/z): 306 (M+1).

Example 7 5-(4-Methoxy-benzoyl)-2-methylsulfanyl-benzenesulfonamide

To a solution of 2-fluoro-5-(4-methoxy-benzoyl)-benzenesulfonamide (0.15g, 0.48 mmol) dissolved in dioxane (3 mL) is added sodium thiomethoxide(0.041 g, 0.57 mmol). The reaction mixture is heated at 90° C. for 4 hand then cooled to room temperature and concentrated in vacuo. Theresidue is partitioned between water and methylene chloride, and theaqueous phase is extracted with methylene chloride three times. Thecombined organic extracts are washed with a saturated sodium chloridesolution, dried with magnesium sulfate, and concentrated in vacuo.Purification by silica gel chromatography (50% ethyl acetate-hexane)gives 0.11 g (68%) of the title compound as a white solid. ¹H NMR(CDCl₃): δ 8.4 (d, J=2 Hz, 1H), 7.90 (dd, J=8, 2 Hz, 1H), 7.80 (d, J=9Hz, 2H), 7.50 (d, J=8 Hz, 1H), 7.00 (d, J=9 Hz, 2H), 5.20 (s, 2H), 3.90(s, 3H), 2.65 (s, 3H). Analytics calculated for C₁₅H₁₅NO₄S₂: C, 53.04;H, 4.48; N, 4.15. Found: C, 52.67; H, 4.57; N, 4.08. MS (m/z): 336(M−1).

Example 8 2-Methanesulfinyl-5-(4-methoxy-benzoyl)-benzenesulfonamide

To a solution of5-(4-methoxy-benzoyl)-2-methylsulfanyl-benzenesulfonamide (0.06 g, 0.18mmol) dissolved in methylene chloride (3 mL) at 0° C. is addedm-chloroperoxybenzoic acid (0.061 g, 0.36 mmol). The reaction mixture isstirred at room temperature for 30 minutes. Then, the reaction isquenched with saturated sodium sulfite and sodium bicarbonate solution.The aqueous layer is extracted with methylene chloride three times. Thecombined organic extracts are washed with a saturated sodium chloridesolution, dried with magnesium sulfate, and concentrated in vacuo.Purification by silica gel chromatography (75% ethyl acetate-hexane)followed by recrystallization (methylene chloride-hexane) provides 0.022g (35%) of the title compound as a pale yellow solid. ¹H NMR (CDCl₃): δ8.35 (d, J=8 Hz, 1H), 8.10 (dd, J=8, 1 Hz, 1H), 7.80 (d, J=9 Hz, 2H),7.00 (d, J=9 Hz, 2H), 5.60 (s, 2H), 3.95 (s, 3H), 3.00 (s, 3H).Analytics calculated for C₁₅H₁₅NO₅S₂: C, 50.98; H, 4.28; N, 3.96. Found:C, 50.17; H, 4.46; N, 3.40. MS (m/z): 352 (M−1).

Example 9 2-Methanesulfonyl-5-(4-methoxy-benzoyl)-benzenesulfonamide

To a solution of5-(4-methoxy-benzoyl)-2-methylsulfanyl-benzenesulfonamide (0.12 g, 0.36mmol) dissolved in methylene chloride (3 mL) at 0° C. is addedm-chloroperoxybenzoic acid (0.153 g, 0.90 mmol). The reaction mixture isstirred at room temperature for 2 h. Then, the reaction is quenched withsaturated sodium sulfite and sodium bicarbonate solution. The aqueouslayer is extracted with methylene chloride three times. The combinedorganic extracts are washed with a saturated sodium chloride solution,dried with magnesium sulfate, and concentrated in vacuo. Purification bysilica gel chromatography (75% ethyl acetate-hexane) followed byrecrystallization (methylene chloride-hexane) provides 0.038 g (28%) ofthe title compound as a pale yellow solid. ¹H NMR (CDCl₃): δ 8.55 (d,J=1 Hz, 1H), 8.40 (d, J=8 Hz, 1H), 8.10 (dd, J=8, 1 Hz, 1H), 7.80 (d,J=8 Hz, 2H), 7.00 (d, J=8 Hz, 2H), 5.80 (s, 2H), 3.95 (s, 3H), 3.44 (s,3H). Analytics calculated for C₁₅H₁₅NO₆S₂: C, 48.77; H, 4.09; N, 3.79.Found: C, 48.51; H, 4.16; N, 3.40. MS (m/z): 368 (M−1).

Example 10 2-Chloro-5-(4-methoxy-benzoyl)-N-phenethyl-benzenesulfonamide

2-Chloro-5-(4-methoxy-benzoyl)-benzenesulfonyl chloride

The title compound is prepared as described above for2-fluoro-5-(4-methoxy-benzoyl)-benzenesulfonyl chloride, starting with4-chloro-benzoic acid.

2-Chloro-5-(4-methoxy-benzoyl)-N-phenethyl-benzenesulfonamide

2-Chloro-5-(4-methoxy-benzoyl)-benzenesulfonyl chloride (0.2 g, 5.79mmol) is dissolved in methylene chloride (10 mL). Phenethylamine (0.077g, 6.36 mmol) is added, followed by the addition of triethylamine (0.146g, 14.5 mmol). The reaction mixture is stirred for 2 h at roomtemperature. Water is added, and the mixture extracted with methylenechloride. The solvent is removed and the mixture is purified by flashcolumn chromatography, using 50% of ethyl acetate-hexane as an eluent.The product is obtained as a colorless oil (0.13 g, 52% yield). ¹H NMR(CDCl₃): δ 8.4 (m, 1H), 7.90 (m, 1H), 7.50 (d, J=8 Hz, 2H), 7.28 (m,3H), 7.00 (d, J=8 Hz, 2H), 7.17 (m, 2H), 4.97 (m, 1H), 3.91 (s, 3H),3.20 (m, 2H), 2.80 (m, 2H). Analytics calculated for C₂₂H₂₀ClNO₄S: C,61.46; H, 4.69; N, 3.26. Found: C, 61.20; H, 4.95; N, 3.10. MS (m/z):430.0 (M+1).

Example 112-Chloro-N-[2-(4-fluoro-phenyl)-ethyl]-5-(4-methoxy-benzoyl)-benzenesulfonamide

The title compound is prepared as described for2-chloro-5-(4-methoxy-benzoyl)-N-phenethyl-benzenesulfonamide, exceptusing 4-fluoro-phenethylamine. ¹H NMR (CDCl₃): δ 8.4 (m, 1H), 7.90 (m,1H), 7.80 (d, J=8 Hz, 2H), 7.60 (m, 1H), 7.08 (m, J=8 Hz, 2H), 7.00 (m,3H), 4.97 (m, 1H), 3.91 (s, 3H), 3.20 (m, 2H), 2.80 (m, 2H). Analyticscalculated for C₂₂H₁₉ClFNO₄S: C, 58.99; H, 4.28; N, 3.13. Found: C,58.58; H, 4.33; N, 3.12. MS (m/z): 448.0 (M+1)⁻.

Example 12 2-Chloro-5-(3-hydroxy-4-methoxy-benzoyl)-benzenesulfonamide

5-Bromo-2-methoxy-phenol

To a solution of 5-bromo-2-methoxy-benzaldehyde (8 g, 4.67 mmol)dissolved in methylene chloride (24 mL) at 0° C. is slowly added asolution of m-chloroperoxybenzoic acid (10.90 g, 5.60 mmol) in methylenechloride (80 mL). The reaction mixture is slowly warmed up to roomtemperature and stirred for 72 h. The white solid is filtered off andthe filtrate is stirred for 2 h with 2 M sodium sulfite (32 mL). Theorganic layer is concentrated in vacuo then the residue is dissolved indiethyl ether and washed with 1 M sodium sulfite and a half-saturatedsodium bicarbonate solution. The organic phase is extracted with 2 Msodium hydroxide. The combined basic extract is acidified to pH 3-4 withconcentrated HCl, and extracted with diethyl ether. The combined organicextracts are washed with a saturated sodium chloride solution, driedwith magnesium sulfate, and concentrated in vacuo to provide 3.5 g (37%)of the title compound as a brown solid. ¹H NMR (CDCl₃): δ 7.10 (d, J=2Hz, 1H), 7.00 (dd, J=8, 2 Hz, 1H), 6.70 (d, J=8 Hz, 1H), 3.95 (s, 3H).

(5-Bromo-2-methoxy-phenoxy)-tert-butyl-dimethyl-silane

To a solution of 5-bromo-2-methoxy-phenol (3.5 g, 17.2 mmol) dissolvedin methylene chloride (50 mL) are added triethylamine (2.08 g, 20.6mmol) and 4-dimethylaminopyridine (0.15 g, 0.86 mmol). Thentert-butyldimethylsilyl chloride is added slowly and the reactionmixture is stirred at room temperature for 16 h. The reaction isquenched with 10% of citric acid, and then the organic layer is washedwith saturated sodium bicarbonate solution, a saturated sodium chloridesolution, dried with magnesium sulfate, and concentrated in vacuo.Purification by silica gel chromatography (15% ethyl acetate-hexane)provides 5.6 g (100%) of the title compound as a colorless oil. ¹H NMR(CDCl₃): δ 6.82 (m, 2H), 6.58 (d, J=9 Hz, 1H), 3.74 (s, 3H), 0.95 (s,9H), 0.05 (s, 6H).

5-{[3-(tert-butyl-dimethyl-silanyloxy)-4-methoxy-phenyl]-hydroxy-methyl}-2-chloro-benzenesulfonamide

To a solution of (5-bromo-2-methoxy-phenoxy)-tert-butyl-dimethyl-silane(2 g, 6.32 mmol) dissolved in tetrahydrofuran (25 mL) at −78° C. undernitrogen is dropwisely added 1.7 M of tert-butyllithium (8.06 mL, 12.6mmol). The reaction mixture is stirred at −78° C. for 5 minutes. Then,the solution of 2-chloro-5-formyl-benzenesulfonamide (0.462 g, 2.11mmol) in tetrahydrofuran (5 mL) is added slowly. The reaction mixture iswarmed up to room temperature and stirred for 24 h. The reaction isquenched with 1 N of HCl, and extracted with ethyl acetate three times.The combined organic extracts are washed with a saturated sodiumchloride solution, dried with magnesium sulfate, and concentrated invacuo. Purification by silica gel chromatography (50% ethylacetate-hexane) provides 0.57 g (59%) of the title compound as a brownoil. ¹H NMR (CDCl₃): δ 8.00 (m, 1H), 7.40 (m, 2H), 6.70 (d, 3H), 5.70(s, 1H), 5.00 (m, 2H), 3.70 (s, 3H), 0.90 (s, 9H), 0.05 (s, 6H).

5-[3-(tert-Butyl-dimethyl-silanyloxy)-4-methoxy-benzoyl]-2-chloro-benzenesulfonamide

To a solution of5-{[3-(tert-butyl-dimethyl-silanyloxy)-4-methoxy-phenyl]-hydroxy-methyl}-2-chloro-benzenesulfonamide(0.57 g, 1.24 mmol) dissolved in acetone (100 mL) is added Jones reagent(3 M, 0.4 mL), and the reaction mixture is stirred at room temperaturefor 15 minutes. The reaction is quenched with water, and the aqueouslayer is extracted with methylene chloride three times. The combinedorganic extracts are washed with saturated sodium bicarbonate solution,a saturated sodium chloride solution, dried with magnesium sulfate, andconcentrated in vacuo. Recrystallization from methylene chloride/hexaneprovides 0.28 g (50%) of the title compound as a grey solid. ¹H NMR(CDCl₃): δ 8.23 (d, J=2 Hz, 1H), 7.80 (dd, J=8, 2 Hz, 1H), 7.50 (d, J=8Hz, 1H), 7.20 (m, 2H), 6.70 (d, J=8 Hz, 1H), 5.00 (s, 2H), 3.70 (s, 3H),0.90 (s, 9H), 0.05 (s, 6H).

2-Chloro-5-(3-hydroxy-4-methoxy-benzoyl)-benzenesulfonamide

To a solution of5-[3-(tert-butyl-dimethyl-silanyloxy)-4-methoxy-benzoyl]-2-chloro-benzenesulfonamide(0.28 g, 0.61 mmol) dissolved in tetrahydrofuran (20 mL) is added 1 Mtetrabutylammonium fluoride (1.23 mL, 1.22 mmol) in tetrahydrofuran. Thereaction mixture is stirred at room temperature for 30 minutes Thereaction is quenched with 1 N of HCl, and extracted with ethyl acetatethree times. The combined organic extracts are washed with a saturatedsodium chloride solution, dried with magnesium sulfate, and concentratedin vacuo. Recrystallization from ethyl acetate/methylene chlorideprovides 0.11 g (49%) of the title compound as a brown solid. ¹H NMR(DMSO): δ 9.60 (s, 1H), 8.20 (d, J=2 Hz, 1H), 7.80 (m, 4H), 7.20 (m,2H), 7.10 (d, J=8 Hz, 1H), 3.90 (s, 3H). Analytics calculated forC₁₄H₁₂ClNO₃S: C, 49.20; H, 3.54; N, 4.10. Found: C, 49.90; H, 3.30; N,5.06. MS (m/z): 342 (M+1).

Example 13 2-Chloro-5-[4-(2-hydroxy-ethoxy)-benzoyl]-benzenesulfonamide

[2-(4-Bromo-phenoxy)-ethoxy]-tert-butyl-dimethyl-silane

2-(4-Bromo-phenoxy)-ethanol (5 g, 23 mmol) is dissolved indichloromethane (40 mL). Triethylamine (2.8 g, 28 mmol) and4-dimethylaminopyridine (140 mg, 1.15 mmol) were then added followed bytert-butyldimethylsilyl chloride (3.65 g, 24.3 mmol) as a solution indichloromethane (10 mL). The reaction is allowed to stir at ambienttemperature for 18 hours. The reaction mixture is washed with 10%aqueous citric acid, the organic layer is separated and concentrated invacuo to afford 7.5 g (98% yield) of the title compound. ¹H NMR (CDCl₃)δ 0.05 (s, 6H), 0.85 (s, 9H), 3.85-3.94 (m, 4H), 6.72 (d, 2H, J=6.90Hz), 7.28 (d, 2H, J=6.90 Hz).

5-{4-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-benzoyl}-2-chloro-benzenesulfonamide

[2-(4-Bromo-phenoxy)-ethoxy]-tert-butyl-dimethyl-silane (7.3 g, 22.12mmol) is dissolved in tetrahydrofuran (120 mL) and cooled to −78° C. Thesolution is treated with a solution of n-butyllithium (1.6 M in hexanes,13.8 mL, 22.12 mmol) and stirred 30 minutes after which a solution of4-chloro-N-methoxy-N-methyl-3-sulfamoyl-benzamide (2.05 g, 7.37 mmol) intetrahydrofuran (20 mL) is added. The reaction is allowed to stir for 18hours while warming to ambient temperature. The reaction is quenchedwith a saturated solution of ammonium chloride and extracted twice withether. The organic phase is separated and concentrated in vacuo. Theresidue is purified by column chromatography (gradient of ethyl acetatein hexanes 10-50%) affording 1.84 g (53% yield) of the title compound.MS (m/z): 470.2 (M+1).

2-Chloro-5-[4-(2-hydroxy-ethoxy)-benzoyl]-benzenesulfonamide

5-{4-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-benzoyl}-2-chloro-benzenesulfonamide(1.84 g, 3.92 mmol) is dissolved in tetrahydrofuran (50 mL), and treatedwith a solution of tetrabutylammonium fluoride reagent (1 M intetrahydrofuran, 2.2 mmol). The reaction is allowed to stir for 1 hour.The reaction is diluted with water and extracted with ether. The organicphase is separated and concentrated in vacuo affording 1.39 g (100%yield) of the title compound. ¹H NMR (DMSO) δ 3.75 (t, 2H, J=4.55 Hz),4.12 (t, 2H, J=4.80 Hz), 4.95 (s, 2H), 7.12 (d, 2H, J=8.84 Hz),7.76-7.90 (m, 4H), 8.24 (d, 1H, J=2.02). MS (m/z): 354 (M−1).

Example 14 2-Chloro-5-(4-butoxy-benzoyl)-benzenesulfonamide

2-Chloro-5-[hydroxy-(4-butoxy-phenyl)-methyl]-benzenesulfonamide

1-Bromo-4-butoxy-benzene (625 mg, 2.73 mmol) is dissolved intetrahydrofuran (2 mL) and cooled to −78° C. The solution is treatedwith a solution of n-butyllithium (1.6 M in hexanes, 1.7 mL, 2.73 mmol)which resulted in precipitation of the aryllithium. The suspension isallowed to warm to ambient temperature and is added via canula to asolution of 2-chloro-5-formyl-benzenesulfonamide (200 mg, 0.91 mmol) intetrahydrofuran (2 mL) at −78° C. The reaction is allowed to warm toambient temperature, at which point it is quenched with a saturatedsolution of ammonium chloride. The tetrahydrofuran is removed in vacuoand the residue is diluted with water and extracted with ethyl acetate.The organic phase is separated and concentrated in vacuo. The residue isused without further purification.

2-Chloro-5-(4-butoxy-benzoyl)-benzenesulfonamide

2-Chloro-5-[hydroxy-(4-butoxy-phenyl)-methyl]-benzenesulfonamide isdissolved in acetone (10 mL), and treated with a solution of Jonesreagent (3 M in water, 0.91 mmol). The reaction is allowed to stir for30 minutes. The reaction is diluted with water and extracted withdichloromethane. The organic phase is separated and concentrated invacuo. The residue is purified by silica gel chromatography (gradient ofethyl acetate in hexanes 10-50%) affording 74 mg of the title compound.¹H NMR (CDCl₃) δ 0.95 (t, 3H, J=7.31 Hz), 1.50 (m, 2H), 1.80 (m, 2H),4.05 (t, 2H, J=6.48 Hz), 5.15 (s, 2H), 6.95 (d, 2H, J=9.04 Hz), 7.65 (d,1H, J=8.22), 7.80 (d, 2H, J=9.04 Hz), 7.90 (dd, 1h, J=1.88, 7.91), 8.45(d, 1H, J=1.88). MS (m/z): 368 (M+1). CHN Calc C, 55.51; H, 4.93; N,3.81. Found C, 55.47; H, 4.84; N, 3.63.

Example 15 2-Chloro-5-(4-isobutoxy-benzoyl)-benzenesulfonamide

1-Bromo-4-isobutoxy-benzene

4-Bromo-phenol (2 g, 11.6 mmol) is dissolved in acetone (40 mL).Potassium carbonate (8 g, 38.4 mmol) is then added followed by isobutylbromide (4 g, 29.2 mmol). The reaction is heated to reflux for fourdays, refilling solvent as necessary. The reaction mixture is dilutedwith water and extracted with ether, the organic layer is separated andconcentrated in vacuo. The residue is dissolved in hexane dried withmagnesium sulfate, and filtered through a plug of silica gel. Thesolvent is removed in vacuo to afford 1.6 g (60% yield) of the titlecompound as a colorless non-viscous oil. ¹H NMR (CDCl₃) δ 1.01 (d, 6H,J=6.56 Hz), 2.05-2.08 (m, 1H), 3.67 (d, 2H, J=6.57 Hz), 6.77 (d, 2H,J=9.09 Hz), 7.36 (d, 2H, J=9.09 Hz).

2-Chloro-5-(4-isobutoxy-benzoyl)-benzenesulfonamide

1-Bromo-4-isobutoxy-benzene (625 mg, 2.73 mmol) is dissolved intetrahydrofuran (2 mL) and cooled to −78° C. The solution is treatedwith a solution of n-butyllithium (1.6 M in hexanes, 1.7 mL, 2.73 mmol)and stirred 30 minutes after which a solution of4-chloro-N-methoxy-N-methyl-3-sulfamoyl-benzamide (250 mg, 0.91 mmol) intetrahydrofuran (2 mL) is added. The reaction is allowed to stir for 18hours while warming to ambient temperature. The reaction is quenchedwith a saturated solution of ammonium chloride and extracted with ethylacetate. The organic phase is separated and concentrated in vacuo. Theresidue is purified by column chromatography (gradient of ethyl acetatein hexanes 10-50%) affording 120 mg (37% yield) of the title compound.¹H NMR (DMSO) δ 1.00 (d, 6H, J=6.56 Hz), 2.01-2.10 (m, 1H), 3.88 (d, 2H,J=6.57 Hz), 7.11 (d, 2H, J=8.85 Hz), 7.76 (d, 2H, J=8.85 Hz), 7.81-7.84(m, 3H), 7.89 (dd, 1H, J=2.02, 8.08), 8.24 (d, 1H, J=2.02). MS (m/z):366 (M−1). CHN Calc C, 55.51; H, 4.93; N, 3.81. Found C, 55.38; H, 4.74;N, 3.77.

Example 16 2-Chloro-5-[4-(3-methyl-butoxy)-benzoyl]-benzenesulfonamide

2-Chloro-5-{hydroxy-[4-(3-methyl-butoxy)-phenyl]-methyl}-benzenesulfonamide

1-Bromo-4-(3-methyl-butoxy)-benzene (665 mg, 2.73 mmol) is dissolved intetrahydrofuran (2 mL) and cooled to −78° C. The solution is treatedwith a solution of n-butyllithium (1.6 M in hexanes, 1.7 mL, 2.73 mmol)which resulted in precipitation of the aryllithium. The suspension isallowed to warm to ambient temperature and is added via canula to asolution of 2-chloro-5-formyl-benzenesulfonamide (200 mg, 0.91 mmol) intetrahydrofuran (2 mL) at −78° C. The reaction is allowed to warm toambient temperature, at which point it is quenched with a saturatedsolution of ammonium chloride. The tetrahydrofuran is removed in vacuoand the residue is diluted with water and extracted with ethyl acetate.The organic phase is separated and concentrated in vacuo. The residue isused without further purification.

2-Chloro-5-[4-(3-methyl-butoxy)-benzoyl]-benzenesulfonamide

2-Chloro-5-{hydroxy-[4-(3-methyl-butoxy)-phenyl]-methyl}-benzenesulfonamideis dissolved in acetone (10 mL), and treated with a solution of Jonesreagent (3 M in water, 0.91 mmol). The reaction is allowed to stir for30 minutes. The reaction is diluted with water and extracted withdichloromethane. The organic phase is separated and concentrated invacuo. The residue is purified by silica gel chromatography (gradient ofethyl acetate in hexanes 25-75%) followed by recrystallization fromether affording 25 mg of the title compound. ¹H NMR (DMSO) δ 0.93 (s,3H), 0.95 (s, 3H), 1.64-1.82 (m, 3H), 4.13 (t, 2H, J=6.41 Hz), 7.12 (d,2H, J=8.67 Hz), 7.75-7.91 (m, 4H), 8.24 (d, 1H, J=1.89). MS (m/z): 380(M−1). CHN Calc C, 56.62; H, 5.28; N, 3.67. Found C, 56.54; H, 5.04; N,3.73.

Example 17 2-Chloro-5-[4-(3-phenyl-propoxy)-benzoyl]-benzenesulfonamide

2-Chloro-N-dimethylaminomethylene-5-(4-hydroxy-benzoyl)-benzenesulfonamide

A solution of N,N,-dimethylformamide dimethyl acetal (1.2 g, 10.1 mmol)in acetonitrile (10 mL) is slowly added to a solution of2-chloro-5-(4-hydroxy-benzoyl)-benzenesulfonamide (2.61 g, 8.4 mmol) inacetonitrile (10 mL). The reaction is allowed to stir for 5 hours atambient temperature. Volatiles were removed in vacuo. The residue ispartitioned between ethyl acetate and water, the organic layer isseparated and the solvent is removed in vacuo, affording 2.5 g (81%yield) of the title compound which is carried on directly in the nextstep.

2-Chloro-5-[4-(3-phenyl-propoxy)-benzoyl]-benzenesulfonamide

2-Chloro-N-dimethylaminomethylene-5-(4-hydroxy-benzoyl)-benzenesulfonamide(250 mg, 0.68 mmol) is dissolved in N,N,-dimethylformamide (5 mL).Potassium carbonate (235 mg, 1.7 mmol) is then added followed by(3-bromo-propyl)-benzene (135 mg, 0.68 mmol). The reaction is heated to65° C. for 18 hours. The reaction mixture is diluted with water andextracted with ethyl acetate, the organic layer is separated andconcentrated in vacuo. The crude ether is purified by columnchromatography (gradient of ethyl acetate in hexanes 25-75%). Theresidue is dissolved in ethanol (3 mL), treated with concentrated HCl(400 μl) and heated to reflux for 2.5 hours after which the reaction isallowed to cool to ambient temperature overnight. The volatiles wereremoved in vacuo and the crude sulfonamide is purified by columnchromatography (gradient of ethyl acetate in hexanes 20-70%) affording10 mg of the title compound. ¹H NMR (DMSO) δ 2.02-2.11 (m, 2H), 2.76 (t,2H, J=7.16 Hz), 4.10 (t, 2H, J=6.41 Hz), 7.10 (d, 2H, J=8.67 Hz),7.17-7.32 (m, 5H), 7.75-7.91 (m, 6H), 8.24 (d, 1H, J=1.88 Hz). MS (m/z):430 (M+1).

Example 18 2-Chloro-5-(4-pentyloxy-benzoyl)-benzenesulfonamide

2-Chloro-5-[(4-pentyloxy-phenyl)-hydroxy-methyl]-benzenesulfonamide

1-Bromo-4-pentyloxy-benzene (656 mg, 2.73 mmol) is dissolved intetrahydrofuran (2 mL) and cooled to −78° C. The solution is treatedwith a solution of n-butyllithium (1.6 M in hexanes, 1.7 mL, 2.73 mmol)which resulted in precipitation of the aryllithium. The suspension isallowed to warm to ambient temperature and is added via canula to asolution of 2-chloro-5-formyl-benzenesulfonamide (200 mg, 0.91 mmol) intetrahydrofuran (2 mL) at −78° C. The reaction is allowed to warm toambient temperature, at which point it is quenched with a saturatedsolution of ammonium chloride. The tetrahydrofuran is removed in vacuoand the residue is diluted with water and extracted with ethyl acetate.The organic phase is separated and concentrated in vacuo. The residue isused without further purification.

2-Chloro-5-(4-pentyloxy-benzoyl)-benzenesulfonamide

2-Chloro-5-[(4-pentyloxy-phenyl)-hydroxy-methyl]-benzenesulfonamide isdissolved in acetone (10 mL), and treated with a solution of Jonesreagent (3 M in water, 0.91 mmol). The reaction is allowed to stir for30 minutes. The reaction is diluted with water and extracted withdichloromethane. The organic phase is separated and concentrated invacuo. The residue is purified by silica gel chromatography (gradient ofethyl acetate in hexanes 25-75%) followed by recrystallization fromether affording 15 mg of the title compound. ¹H NMR (DMSO) δ 0.90 (t,3H, J=6.79 Hz), 1.31-1.46 (m, 4H), 1.70-1.79 (m, 2H), 4.09 (t, 2H,J=6.49 Hz), 7.10 (d, 2H, J=9.04 Hz), 7.75-7.90 (m, 4H), 8.24 (d, 1H,J=1.89). MS (m/z): 382 (M+1).

Example 19 2-Chloro-5-(4-hexyloxy-benzoyl)-benzenesulfonamide

2-Chloro-5-[(4-hexyloxy-phenyl)-hydroxy-methyl]-benzenesulfonamide

1-Bromo-4-hexyloxy-benzene (695 mg, 2.73 mmol) is dissolved intetrahydrofuran (2 mL) and cooled to −78° C. The solution is treatedwith a solution of n-butyllithium (1.6 M in hexanes, 1.7 mL, 2.73 mmol)which resulted in precipitation of the aryllithium. The suspension isallowed to warm to ambient temperature and is added via canula to asolution of 2-chloro-5-formyl-benzenesulfonamide (200 mg, 0.91 mmol) intetrahydrofuran (2 mL) at −78° C. The reaction is allowed to warm toambient temperature, at which point it is quenched with a saturatedsolution of ammonium chloride. The tetrahydrofuran is removed in vacuoand the residue is diluted with water and extracted with ethyl acetate.The organic phase is separated and concentrated in vacuo. The residue isused without further purification.

2-Chloro-5-(4-hexyloxy-benzoyl)-benzenesulfonamide

2-Chloro-5-[(4-hexyloxy-phenyl)-hydroxy-methyl]-benzenesulfonamide isdissolved in acetone (10 mL), and treated with a solution of Jonesreagent (3 M in water, 0.91 mmol). The reaction is allowed to stir for30 minutes. The reaction is diluted with water and extracted withdichloromethane. The organic phase is separated and concentrated invacuo. The residue is purified by silica gel chromatography (gradient ofethyl acetate in hexanes 25-75%) followed by recrystallization fromether affording 30 mg of the title compound. ¹H NMR (DMSO) δ 0.88 (t,3H, J=6.78 Hz), 1.28-1.45 (m, 6H), 1.70-1.79 (m, 2H), 4.09 (t, 2H, J=6.4Hz), 7.10 (d, 2H, J=9.04 Hz), 7.75-7.90 (m, 4H), 8.24 (d, 1H, J=1.89).MS (m/z): 396 (M+1).

Example 20 2-Chloro-5-(4-trifluoromethoxy-benzoyl)-benzenesulfonamide

2-Chloro-5-[hydroxy-(4-trifluoromethoxy-phenyl)-methyl]-benzenesulfonamide

1-Bromo-4-trifluoromethoxy-benzene (660 mg, 2.73 mmol) is dissolved intetrahydrofuran (2.5 mL) and cooled to −78° C. The solution is treatedwith a solution of n-butyllithium (1.6 M in hexanes, 1.7 mL, 2.73 mmol)which resulted in precipitation of the aryllithium. The suspension isallowed to warm to ambient temperature and is added via canula to asolution of 2-chloro-5-formyl-benzenesulfonamide (200 mg, 0.91 mmol) intetrahydrofuran (2.5 mL) at −78° C. The reaction is allowed to warm toambient temperature, at which point it is quenched with a saturatedsolution of ammonium chloride. The tetrahydrofuran is removed in vacuoand the residue is diluted with water and extracted with ethyl acetate.The organic phase is separated and concentrated in vacuo. The residue isused without further purification.

2-Chloro-5-(4-trifluoromethoxy-benzoyl)-benzenesulfonamide

2-Chloro-5-[hydroxy-(4-trifluoromethoxy-phenyl)-methyl]-benzenesulfonamideis dissolved in acetone (10 mL), and treated with a solution of Jonesreagent (3 M in water, 0.91 mmol). The reaction is allowed to stir for30 minutes. The reaction is diluted with water and extracted withdichloromethane. The organic phase is separated and concentrated invacuo. The residue is purified by silica gel chromatography (gradient ofethyl acetate in hexanes 10-50%) affording 92 mg of the title compound.¹H NMR (CDCl₃) δ 5.20 (s, 2H), 7.35 (d, 2H, J=8.3 Hz), 7.70 (d, 1H,J=8.3), 7.84 (d, 2H, J=8.7 Hz), 7.95 (dd, 1h, J=1.9, 8.3), 8.48 (d, 1H,J=1.9). MS (m/z): 378 (M−1). CHN Calc C, 44.28; H, 2.39; N, 3.69. FoundC, 43.97; H, 2.22; N, 3.60.

Example 21 2-Chloro-5-(4-phenylethynyl-benzoyl)-benzenesulfonamide

To a degassed solution of5-(4-bromo-benzoyl)-2-chloro-benzenesulfonamide (500 mg, 1.33 mmol),phenylacetylene (204 mg, 2.00 mmol), copper iodide (15 mg),triphenylphosphine (9 mg, 0.033 mmol) and triethylamine (0.278 mL, 2mmol) in tetrahydrofuran (4 mL) is addeddichlorobis(triphenylphosphine)-palladium (47 mg, 0.067 mmol). Thereaction mixture is allowed to stir at room temperature for 18 hoursthen poured into water (25 mL) and extracted twice with ethyl acetate.The organic fractions are combined, washed twice with a saturated sodiumchloride solution, dried with magnesium sulfate, filtered andconcentrated in vacuo. The resulting residue is purified via silica gelchromatography (20-50% ethyl acetate in hexanes) to yield the titlecompound as a white solid. MS (m/z): 394 (M−1).

Example 224-(4-Chloro-3-sulfamoyl-benzoyl)-N-(2-pyridin-2-yl-ethyl)-benzamide

4-(4-Chloro-3-sulfamoyl-benzoyl)-N-(2-pyridin-2-yl-ethyl)-benzamide

4-(4-Chloro-3-sulfamoyl-benzoyl)-benzoic acid (50 mg, 0.15 mmol),1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (57 mg, 0.30 mmol),1-hydroxy-7-azabenzotriazole (41 mg, 0.30 mmol) were dissolved indichloromethane (5 mL), then triethylamine (61 mg, 0.60 mmol) is addedfollowed by 2-pyridin-2-yl-ethylamine (23 mg, 0.19 mL) and the reactionis allowed to stir at ambient temperature overnight. The reaction isthen quenched with trifluoroacetic acid (1 mmol) and loaded directlyonto a silica gel column, chromatography (gradient of ethyl acetate inhexanes 10-100%) followed by crystallization from ether afforded 20 mgof the title compound. ¹H NMR (DMSO) δ 3.02 (t, 2H, J=7.57 Hz),3.63-3.68 (m, 2H), 7.22-7.25 (m, 1H), 7.30 (d, 1H, J=7.83 Hz), 7.70-7.74(m, 1H), 7.83-7.87 (m, 5H), 7.92-7.99 (m, 3H), 8.31 (d, 1H, J=2.02),8.51-8.53 (m, 1H), 8.85-8.82 (m, 1H). MS (m/z): 442 (M−1). CHN Calc C,56.82; H, 4.09; N, 9.47. Found C, 55.65; H, 3.90; N, 9.22 (+0.5 water).

Example 23 2-Chloro-5-(4-pyrrolidin-1-yl-benzoyl)benzenesulfonamide

1-(4-Bromo-phenyl)-pyrrolidine

A oven-dried 50 mL of round bottom flask is charged with Pd₂(dba)₃ (116mg, 0.13 mmol), BINAP (158 mg, 0.25 mmol), and sodium tert-butoxide (916mg, 9.54 mmol). The flask is evacuated and backfilled with argon.Degassed toluene (5 mL), 1-iodo-4-bromobenzene (1.8 g, 6.36 mmol),pyrrolidine (542 mg, 7.63 mmol) are then added. The mixture is heated at80° C. until the starting aryl iodide is completed consumed judged byLC-MS analysis. The mixture is diluted with ethyl acetate, filteredthrough Celite, and concentrated in vacuo. The crude product is purifiedby flash chromatography to give 1.1 g of product as light brown solid.¹H NMR (400 MHz, CDCl₃): δ 2.00 (t, 4H, J=4 Hz), 3.24 (t, 4H, J=4 Hz),6.42 (d, 2H, J=8 Hz), 7.29 (d, 2H, J=8 Hz).

2-Chloro-5-(4-pyrrolidin-1-yl-benzoyl)-benzenesulfonamide

Following method C, 1-(4-bromo-phenyl)-pyrrolidine is converted into thetitle compound. ¹H NMR (400 MHz, CDCl₃): δ 2.06 (t, 4H, J=8 Hz), 3.40(t, 4H, J=8 Hz), 5.19 (s, 2H), 6.55 (d, 2H, J=6 Hz), 7.63 (d, 1H, J=8Hz), 7.72 (d, 2H, J=8 Hz), 7.86 (d, 1H, J=8 Hz), 8.41 (s, 1H). MS (m/z):365 (M+1).

Example 242-Chloro-5-[4-(2,5-dihydro-pyrrol-1-yl)-benzoyl]-benzenesulfonamide

Following method B,2-chloro-5-((4-diallylamino-phenyl)-hydroxy-methyl)-benzenesulfonamideis synthesized from the appropriate aryl iodide.

2-Chloro-5-{[4-(2,5-dihydro-pyrrol-1-yl)-phenyl]-hydroxy-methyl}-benzenesulfonamide

A solution of 100 mg of2-chloro-5-((4-diallylamino-phenyl)-hydroxy-methyl)-benzenesulfonamide(0.25 mmol, 1 equivalent) in 5 mL of chloroform is degassed with argonfor 5 minutes, then 5 mg of Grubb's catalyst (0.005 mmol, 2% mmol) isadded. The reaction mixture is stirred at room temperature for 1 h, thendiluted with dichloromethane, filtered through Celite, and a pad ofsilica gel, then concentrated in vacuo to give 70 mg of the titlecompound which is carried forward without further purification.

2-Chloro-5-[4-(2,5-dihydro-pyrrol-1-yl)-benzoyl]-benzenesulfonamide

Following method B the title compound is prepared from2-chloro-5-{[4-(2,5-dihydro-pyrrol-1-yl)-phenyl]-hydroxy-methyl}-benzenesulfonamide.¹H NMR (400 MHz, CDCl₃): δ 0.92 (s, 4H), 5.28 (m, 2H), 6.42 (s, 2H),7.180 (t, 1H, J=2 Hz), 7.55-7.7 (m, 3H), 7.85-8.05 (m, 2H). MS (m/z):361 (M−1).

Example 25 2-Chloro-5-(4-piperidin-1-yl-benzoyl)-benzenesulfonamide

A solution of 300 mg of 4-chloro-3-sulfamoyl-benzoyl chloride (1.186mmol, 1 equivalent) in 20 mL of dichloromethane is stirred at roomtemperature as 2.37 mL of diethyl aluminum chloride (1.0 M in hexane) isadded drop-wise. The reaction is stirred at room temperature for 10minutes, then 229 mg of 1-phenyl piperidine is added. The reaction isstirred at room temperature for 30 minutes. The reaction mixture ispoured onto ice-2 N HCl and extracted with dichloromethane. The aqueouslayer is then basified with 2 N sodium hydroxide and extracted withdichloromethane. The combined organic extracts are washed with water,dried over sodium sulfate, and concentrated in vacuo. After purificationby flash chromatography, 180 mg of product is obtained. ¹H NMR (400 MHz,CDCl₃): δ 1.69 (s, 6H), 3.18 (m, 1H), 3.42 (s, 3H), 5.18 (s, 2H), 6.86(d, 2H, J=8 Hz), 7.62 (d, 1H, J=8 Hz), 7.70 (d, 2H, J=8 Hz), 7.87 (d,1H, J=8 Hz), 8.42 (s, 1H). MS (m/z): 379 (M+1). Analytics calculated forC₁₈H₁₉ClN₂O₃S: C, 57.06; H, 5.05; N, 7.39. Found: C, 56.88; H, 5.04; N,7.13.

Example 262-Chloro-5-[4-(3-methyl-piperidin-1-yl)-benzoyl]-benzenesulfonamide

Preparation of 1-(4-bromo-phenyl)-3-methyl-piperidine

1-(4-Bromo-phenyl)-3-methyl-piperidine is prepared from 0.25 mL of3-methylpiperidine according to the procedure described in example 25.MS (m/z): 255 (M+1).

A solution of 0.821 g of 1-(4-bromo-phenyl)-3-methyl-piperidine intetrahydrofuran is cooled to −78° C. and treated with 0.3 g of4-chloro-N-methoxy-N-methyl-3-sulfamoyl-benzamide. The mixture isstirred for 10 min and treated slowly with 4.31 mL of a solution oftert-butyl lithium (1.5 M) in tetrahydrofuran (3 mL). The orangesolution is stirred at −78° C. for 15 min then at 0° C. for 1 hour. Thereaction mixture is quenched with saturated aqueous ammonium chloride(100 mL) and extracted with ethyl acetate (2×50 mL). The organics arewashed with water, a saturated sodium chloride solution, dried oversodium sulfate, filtered and concentrated in vacuo. The residue isloaded on Celite and purified by silica gel chromatography (1:1hexanes/ethyl acetate) to give2-chloro-5-[4-(3-methyl-piperidin-1-yl)-benzoyl]-benzenesulfonamide as alight yellow syrup. MS (m/z): 393 (M+1). HPLC Reverse Phase (Nucleosil100-5 C18, gradient 10->100% CH₃CN in 5 min) room temperature=5.40minutes.

Example 272-Chloro-5-[4-(4-phenyl-piperidin-1-yl)-benzoyl]-benzenesulfonamide

A solution of 0.227 g of 1-(4-bromo-phenyl)-4-phenyl-piperidine intetrahydrofuran (5 mL) is cooled to −78° C. and treated with 2 portionsof 0.29 mL each of tert-butyllithium (1.5 M in pentane). After 20 min at−78° C. the reaction mixture is treated with 0.1 g of4-chloro-N-methoxy-N-methyl-3-sulfamoyl-benzamide in tetrahydrofuran (5mL) and stirred for another 1.5 h. The temperature is then increasedslowly to 0° C. and after completion the reaction is quenched byaddition of 2 mL of saturated aqueous ammonium chloride and extractedwith diethyl ether. The organics are washed with water, dried overmagnesium sulfate, concentrated to 0.27 g of crude product which ispurified by silica gel chromatography (1:1 hexanes/ethyl acetate) togive 2-chloro-5-[4-(4-phenyl-piperidin-1-yl)-benzoyl]-benzenesulfonamideas a powder. MS (m/z): (M−1) 453; Rf 0.65 (1:1 hexanes/ethyl acetate)

Example 282-Chloro-5-[4-(4-methyl-piperazin-1-yl)-benzoyl]-benzenesulfonamide

A solution of 0.275 g of 1-(4-bromo-phenyl)-4-methyl-piperazine intetrahydrofuran (90 mL) is cooled to −78° C. and treated with 1.44 mL oftert-butyllithium (1.5 M in pentane). After 15 min at −78° C. thereaction mixture is treated with 0.1 g of4-chloro-N-methoxy-N-methyl-3-sulfamoyl-benzamide in tetrahydrofuran (3mL). The temperature is then increased slowly to 0° C. and aftercompletion the reaction is quenched by addition of 2 mL of saturatedaqueous ammonium chloride and extracted with diethyl ether. The organicsare washed with water, dried (magnesium sulfate) and concentrated togive 0.32 g of crude product which is purified by silica gelchromatography (95:5 methylene chloride/methanol) to give2-chloro-5-[4-(4-methyl-piperazin-1-yl)-benzoyl]-benzenesulfonamide as atan powder. MS (m/z): 394 (M+1); Rf 0.06 (95:5 methylenechloride/methanol).

Example 29 2-Chloro-5-(indane-5-carbonyl)-benzenesulfonamide

2-Chloro-5-(indane-5-carbonyl)-benzenesulfonamide

Under nitrogen, aluminum chloride (315 mg, 2.4 mmol) is slurried indichloromethane (20 mL) then 3-chlorosulfonyl-benzoyl chloride (200 mg,0.79 mmol) is added and the reaction is allowed to stir at ambienttemperature for 10 minutes. Indan (100 mg, 0.79 mmol) is added. Thereaction is allowed to stir at ambient temperature for 18 hours. Thereaction mixture is poured over ice-water and extracted withdichloromethane. The organic layer is concentrated to give 265 mg of thetitle compound (100% yield). ¹H NMR (CDCl₃, 300 MHz): δ 8.47 (d, 1H,J=2.19 Hz), 7.93 (dd, 1H, J=2.19, 8.33 Hz), 7.67 (d, 1H, J=8.11), 7.64(s, 1H), 7.53 (d, 1H, J=7.89 Hz), 7.33 (d, 1H, J=7.89 Hz), 5.17 (s, 2H),2.98 (m, 4H), 2.15 (m, 2H). M.P.: 164-166° C. MS (m/z): 336 (M+1).

Example 30 2-Chloro-5-(1H-pyrrole-3-carbonyl)-benzenesulfonamide

1-Benzenesulfonyl-1H-pyrrole

To a well-agitated suspension of sodium hydroxide (4.46 g, 111 mmol) inmethylene chloride (26 mL) at 0° C. is added pyrrole (2.5 g, 0.37 mmol),and the reaction mixture is stirred for 10 min, following which asolution of benzenesulfonyl chloride (7.86 g, 0.44 mmol) in methylenechloride (5.15 mL) is slowly added, allowed to warm to room temperatureand stirred overnight. The reaction is quenched by pouring into water(100 mL). The organic layer is separated, and the aqueous layer isextracted with methylene chloride three times. The combined organicextracts are water, dried with sodium sulfate, and concentrated invacuo. Purification by silica gel chromatography (10% ethylacetate-hexane) provides 4.6 g (60%) of the title compound as a whitesolid. ¹H NMR (CDCl₃): δ 7.80 (m, 2H), 7.50 (m, 3H), 7.25 (m, 2H), 6.30(m, 2H).

5-(1-Benzenesulfonyl-1H-pyrrole-3-carbonyl)-2-chloro-benzenesulfonamide

To a suspension of aluminum chloride (1.89 g, 14 mmol) in methylenechloride (10 mL) is added 4-chloro-3-sulfamoyl-benzoyl chloride (2 g,7.9 mmol). The reaction mixture is stirred at room temperature for 10minutes then a solution of 1-benzenesulfonyl-1H-pyrrole (1.13 g, 5.45mmol) in methylene chloride (3.3 mL) is added. After stirring at roomtemperature overnight, the reaction is quenched with 6 N HCl andextracted with ethyl acetate three times. The combined organic layersare washed with a saturated sodium chloride solution, dried withmagnesium sulfate and concentrated in vacuo. Purification by silica gelchromatography (ethyl acetate/hexane: 2:8) provides 0.6 g (26%) of thetitle compound as a yellow solid. ¹H NMR (DMSO): δ 8.30 (s, 1H), 8.15(m, 2H), 8.05 (m, 2H), 7.80 (m, 4H), 7.70 (m, 2H), 7.40 (m, 1H), 6.70(m, 1H).

2-Chloro-5-(1H-pyrrole-3-carbonyl)-benzenesulfonamide

5-(1-Benzenesulfonyl-1H-pyrrole-3-carbonyl)-2-chloro-benzenesulfonamide(0.1 g, 0.23 mmol) is dissolved in 3 mL of 2:1 (v:v) mixture of methanoland 5 N aqueous sodium hydroxide and heated at reflux for 20 minutesthen the reaction mixture is allowed to cool down and the organicsolvent is removed in vacuo. The aqueous solution is acidified with 5 NHCl to pH 3, thoroughly extracted with ethyl acetate, then the combinedorganic extracts are washed with water, a saturated sodium chloridesolution, dried with magnesium sulfate, and concentrated in vacuo.Recrystallization from ethyl acetate/methylene chloride provides 43 mg(66%) of the title compound as a white solid. ¹H NMR (DMSO): δ 11.70 (s,1H), 8.70 (m, 1H), 8.00 (m, 1H), 7.80 (m, 3H), 7.50 (m, 1H), 7.00 (m,1H), 6.60 (m, 1H). MS (m/z): 285 (M+1) Analytics calculated ForC₁₁H₉N₂ClO₃S: C, 46.40; H, 3.19; N, 9.84. Found: C, 45.84; H, 2.90; N,9.41.

Example 31 2-Chloro-5-(thiophene-2-carbonyl)-benzenesulfonamide

2-Chloro-5-(thiophene-2-carbonyl)-benzenesulfonamide

To a solution of thiophene (0.27 g, 3.20 mmol) dissolved intetrahydrofuran (10 mL) at −78° C. under nitrogen is dropwisely added1.6 M of n-butyllithium (2 mL, 3.40 mmol). The reaction mixture isstirred at −78° C. for 1 h then a solution4-chloro-N-methoxy-N-methyl-3-sulfamoyl-benzamide (0.3 g, 1.08 mmol) intetrahydrofuran (2 mL) is added slowly and the reaction mixture isallowed to warm to room temperature and stirred for 1 h. The reaction isquenched with saturated ammonium chloride and extracted with ethylacetate three times. The combined organic extracts are washed with asaturated sodium chloride solution, dried with magnesium sulfate, andconcentrated in vacuo. Purification by silica gel chromatography (50%ethyl acetate-hexane) provides 0.059 g (18%) of the title compound as ayellow solid. ¹H NMR (DMSO): δ 8.33 (d, J=2 Hz, 1H), 8.15 (dd, J=4, 1Hz, 1H), 8.05 (dd, J=8, 4 Hz, 1H), 7.85 (m, 4H), 7.35 (m, 1H). Analyticscalculated for C₁₁H₈ClO₃S₂: C, 43.78; H, 2.67; N, 4.64. Found: C, 43.70;H, 2.61; N, 4.61. MS (m/z): 300.0 (M−1).

Example 322-Chloro-5-(2-methyl-3H-benzoimidazole-5-carbonyl)-benzenesulfonamide

A solution of 0.303 g of 6-bromo-2-methyl-1H-benzoimidazole intetrahydrofuran (20 mL) is cooled to −50° C. and treated with 2.7 mL oftert-butyllithium (1.5 M in pentane). After 2 h at −50° C. the reactionmixture is treated with 0.12 g of4-chloro-N-methoxy-N-methyl-3-sulfamoyl-benzamide in tetrahydrofuran (10mL). After 3 h the mixture is quenched with saturated aqueous ammoniumchloride, taken up in ethyl acetate, and washed with saturated aqueoussodium chloride. The organics are dried (magnesium sulfate),concentrated and purified by silica gel chromatography (98:2 methylenechloride/methanol) to give2-chloro-5-(2-methyl-3H-benzoimidazole-5-carbonyl)-benzenesulfonamide.MS (m/z): 348 (M−1); Rf 0.30 (9:1 methylene chloride/methanol).

Example 33 5-(9H-Carbazole-2-carbonyl)-2-chloro-benzenesulfonamide

A mixture of 0.5 g of5-(9-acetyl-9H-carbazole-2-carbonyl)-2-chloro-benzenesulfonamide and 20mL of potassium hydroxide solution (10% in water) is heated at refluxovernight and is allowed to cool to room temperature. The reactionmixture is extracted with ethyl acetate, washed with water then asaturated sodium chloride solution, and dried over sodium sulfate. Afterconcentration the residue is loaded on Celite and purified by silica gelchromatography (1:1 hexanes/ethyl acetate) to give5-(9H-carbazole-2-carbonyl)-2-chloro-benzenesulfonamide as dark orangecrystals. MS (m/z): 385 (M+1).

Preparation of5-(9-acetyl-9H-carbazole-2-carbonyl)-2-chloro-benzenesulfonamide

To a solution of 1 g of 1-carbazol-9-yl-ethanone and 2.43 g of4-chloro-3-sulfamoyl-benzoyl chloride in methylene chloride (20 mL) isadded 2.55 g of aluminum chloride. The mixture is stirred at 50° C.overnight. The solution is then cooled at −78° C., quenched with a 6 NHCl solution and allowed to warm up to room temperature. Methylenechloride is added to dissolve the precipitate and the solution isextracted, washed with a saturated sodium chloride solution, dried oversodium sulfate, filtered and concentrated. The residue is loaded onCelite and purified by silica gel chromatography (1:1 hexanes/ethylacetate) to afford5-(9-acetyl-9H-carbazole-2-carbonyl)-2-chloro-benzenesulfonamide asyellow foam. MS (m/z): 427 (M+1). HPLC Reverse Phase (Nucleosil 100-5C18, gradient 10->100% CH₃CN in 5 min) room temperature=5.35 minutes.

Example 34 and Example 358-(4-Chloro-3-sulfamoyl-benzoyl)-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylicacid ethyl ester and7-(4-chloro-3-sulfamoyl-benzoyl)-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylicacid ethyl ester

A mixture of5-benzenesulfonyl-8-(4-chloro-3-sulfamoyl-benzoyl)-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylicacid ethyl ester and5-benzenesulfonyl-7-(4-chloro-3-sulfamoyl-benzoyl)-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylicacid ethyl ester (1 g) is dissolved in 5 mL oftetrahydrofuran-methanol-water (10:10:1) and treated with 0.344 g ofpotassium carbonate. The reaction mixture is heated at 140° C. for 15min (microwave irradiation), filtered and concentrated. The residue ispurified on reverse phase HPLC to give pure8-(4-chloro-3-sulfamoyl-benzoyl)-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylicacid ethyl ester MS (m/z): 462 (M+1); and7-(4-chloro-3-sulfamoyl-benzoyl)-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylicacid ethyl ester MS (m/z): 462 (M+1); both as yellow syrups. Bothisomers are separated by HPLC (Chiracel OD-H 250-4.6 mm, flow 1 ml/Min,UV 235 nM, gradient hexane-ethanol 70-30). The retention times are 6.91min for8-(4-chloro-3-sulfamoyl-benzoyl)-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylicacid ethyl ester and 10.20 min for7-(4-chloro-3-sulfamoyl-benzoyl)-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylicacid ethyl ester.

Preparation of5-benzenesulfonyl-8-(4-chloro-3-sulfamoyl-benzoyl)-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylicacid ethyl ester and5-benzenesulfonyl-7-(4-chloro-3-sulfamoyl-benzoyl)-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylicacid ethyl ester Step 1

A solution of 3 g of 1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylicacid ethyl ester in methylene chloride (50 mL) is treated with 0.982 gof sodium hydroxide and stirred and room temperature overnight.Benzenesulfonylchloride (6.30 mL) is added to the reaction and stirredat room temperature overnight. The reaction mixture is diluted withwater (250 mL) and extracted with methylene chloride. The organics arecombined, washed with water then a saturated sodium chloride solution,dried over sodium sulfate and concentrated in vacuo. The residue isloaded on Celite and purified by silica gel chromatography (1:1hexanes/ethyl acetate) to give5-benzenesulfonyl-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylicacid ethyl ester as a yellow powder. MS (m/z): 385 (M+1).

Step 2

The mixture of regioisomers5-benzenesulfonyl-8-(4-chloro-3-sulfamoyl-benzoyl)-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylicacid ethyl ester and5-benzenesulfonyl-7-(4-chloro-3-sulfamoyl-benzoyl)-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylicacid ethyl ester is prepared from 0.5 g of5-benzenesulfonyl-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carboxylicacid ethyl ester according to the procedure described in example 102. MS(m/z): 603 (M+1).

Example 362-Chloro-5-(1-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carbonyl)-benzenesulfonamide

2,3-Piperidinedione 3-(3-bromophenyl) hydrazone

3-Carbethoxy-2-piperidone (4.7 g, 27.4 mmol) is stirred with potassiumhydroxide (1.64 g) in water (56 mL) and kept at 30° C. on an oil bathovernight. 3-Bromoaniline (4.99 g, 29 mmol) is treated with water (50mL) and concentrated HCl (10 mL) and cooled to 0° C. Sodium nitrite(2.46 g, 35 mmol) in water (9 mL) is added dropwise to the abovesolution at 0° C. and stirred for an additional 20 minutes. Urea isadded to decompose the excess nitrous acid, and the diazotized solutionis neutralized with 10% aqueous sodium carbonate solution (45-50 mL).The resulting solution is filtered into the solution of previouslyhydrolyzed 3-carbethoxy-2-piperidone (2-piperidone-3-carboxylic acid) at0° C. After a few minutes, glacial acetic acid is added to bring the pHof the solution to 3-4. The reaction mixture is stirred at 0° C. for 5-6h, and the yellow precipitate which resulted is filtered, washed withwater, and dried to get the title compound (2.5 g, 32% yield).

7-Bromo-2,3,4,9-tetrahydro-pyrido[3,4-b]indol-1-one

A solution of 2,3-piperidinedione 3-(3-bromophenyl) hydrazone (2.5 g,22.3 mmol) in formic acid (40 mL) is refluxed for 1 h then cooled toroom temperature. The reaction mixture is neutralized with sodiumcarbonate to basic condition. The resulting precipitate is filtered andcollected. Recrystallization with ethanol provides 1.0 g (56%) of thetitle compound as a yellow solid.

7-Trimethylstannanyl-2,3,4,9-tetrahydro-pyrido[3,4-b]indol-1-one

7-Bromo-2,3,4,9-tetrahydro-pyrido[3,4-b]indol-1-one (0.42 g, 1.59 mmol)and hexamethylditin (0.64 g, 1.96 mmol) are dissolved in deoxygenatedtoluene (16 mL) under a nitrogen atmosphere. Palladiumtetrakis(triphenylphosphine) (0.118 g, 0.11 mmol) is added, and themixture is heated at reflux for 7 h. The reaction mixture is partitionedbetween pH 7 buffer and ethyl acetate, and the aqueous layer isextracted with ethyl acetate three times. The combined organics aredried over magnesium sulfate and concentrated in vacuo. The titlecompound is obtained as the yellow oil, which is used in the next stepwithout further purification.

2-Chloro-5-(1-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carbonyl)-benzenesulfonamide

7-Trimethylstannanyl-2,3,4,9-tetrahydro-pyrido[3,4-b]indol-1-one (0.66g, 1.88 mmol) and 1,8-bis(dimethylamino) naphthalene (0.210 g, 0.94mmol) in tetrahydrofuran (25 mL) is treated with4-chloro-3-sulfamoyl-benzoyl chloride (0.48 g, 1.88 mmol). After a fewminutes, allylpalladium chloride dimer (0.057 g, 0.15 mmol) is added.The reaction mixture is stirred for 5 min at room temperature and thenrefluxed for 2 h. After cooling to room temperature the reaction mixtureis diluted with methylene chloride and washed with a saturated sodiumchloride solution then concentrated in vacuo. Purification by silica gelchromatography (75% ethyl acetate-hexane) followed by recrystallization(ethanol-ethyl acetate) provides 0.014 g (1.8%) of the title compound asa pale yellow solid. ¹H NMR (DMSO): δ 12.00 (s, 1H), 8.30 (s, 1H), 8.00(m, 1H), 7.90 (m, 6H), 7.60 (m, 1H), 3.40 (m, 2H), 3.00 (m, 2H). MS(m/z): 402.0 (M−1).

Example 372-Chloro-5-[2-(2,2-dimethyl-propionyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-6-carbonyl]-benzenesulfinamide

2,2-Dimethyl-1-(1,3,4,9-tetrahydro-pyrido[3,4-b]indol-2-yl)-propan-1-one

To a solution of 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (2 g, 11.6mmol) dissolved in methylene chloride (20 mL) is added2,2-dimethyl-propionyl chloride (1.42 mL, 11.6 mmol) followed by theaddition of triethylamine (1.61 mL, 11.6 mmol). The reaction mixture isstirred at room temperature for 30 minutes. The reaction is quenchedwith water and extracted with methylene chloride three times. Thecombined organic extracts are washed with saturated sodium bicarbonate,a saturated sodium chloride solution, dried with magnesium sulfate, andconcentrated in vacuo to give 2.8 g (94%) of the title compound as agrey solid.

1-(9-Benzenesulfonyl-1,3,4,9-tetrahydro-pyrido[3,4-b]indol-2-yl)-2,2-dimethyl-propan-1-one

To a well-agitated suspension of sodium hydroxide (0.81 g, 20.2 mmol) inmethylene chloride (10 mL) is added2,2-dimethyl-1-(1,3,4,9-tetrahydro-pyrido[3,4-b]indol-2-yl)-propan-1-one(2.3 g, 8.98 mmol). The reaction mixture is stirred for 15 min, and thenbenzenesulfonyl chloride (1.89 g, 10.7 mmol) is added. The solution isstirred at room temperature for 1 h. The reaction is diluted withmethylene chloride, washed with water then a saturated sodium chloridesolution, dried with sodium sulfate and concentrated in vacuo.Purification by silica gel chromatography (50% ethyl acetate-hexane)provides 2.0 g (56.2%) of the title compound as a white solid.

5-[9-Benzenesulfonyl-2-(2,2-dimethyl-propionyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-6-carbonyl]-2-chloro-benzenesulfinamideand5-[9-Benzenesulfonyl-2-(2,2-dimethyl-propionyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-7-carbonyl]-2-chloro-benzenesulfinamide

To a suspension of aluminum chloride (0.338 g, 2.54 mmol) in methylenechloride (10 mL) is added 4-chloro-3-sulfamoyl-benzoyl chloride (0.36 g,1.41 mmol). The reaction mixture is stirred at room temperature for 15min then1-(9-benzenesulfonyl-1,3,4,9-tetrahydro-pyrido[3,4-b]indol-2-yl)-2,2-dimethyl-propan-1-oneis added. After the mixture is stirred at room temperature overnight,the reaction is quenched with 6 N HCl and extracted with methylenechloride three times. The combined organic layers are washed with asaturated sodium chloride solution, dried with magnesium sulfate, andconcentrated in vacuo. Purification by silica gel chromatography (ethylacetate/hexane: 2:8) provides 0.12 g (13.8%) of the two title compoundsas a yellow solid.

2-Chloro-5-[2-(2,2-dimethyl-propionyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-6-carbonyl]-benzenesulfinamide

5-[9-Benzenesulfonyl-2-(2,2-dimethyl-propionyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-6-carbonyl]-2-chloro-benzenesulfinamideand its isomer (0.12 g, 0.195 mmol) are dissolved in 3 mL of 2:1 (v:v)mixture of methanol and 5 N aqueous sodium hydroxide then heated atreflux for 20 minutes. The reaction mixture is allowed to cool to roomtemperature and the methanol is removed in vacuo. The aqueous solutionis acidified with 5 N HCl to pH 3 and then thoroughly extracted withethyl acetate, the combined organic extracts are washed with water thena saturated sodium chloride solution, dried with magnesium sulfate, andconcentrated in vacuo. Purification via preparative HPLC provides 0.014g (15%) of the title compound as a yellow solid. ¹H NMR (DMSO): δ 11.40(s, 1H), 8.30 (s, 1H), 7.90 (m, 2H), 7.80 (m, 3H), 7.50-7.60 (m, 2H),4.74 (s, 2H), 4.00 (m, 2H), 2.80 (m, 2H). MS (m/z): 472.1 (M−1).

Example 382-Chloro-5-(1-methyl-2-oxo-2,3,4,9-tetrahydro-1H-indeno[2,1-b]pyridine-7-carbonyl)-benzenesulfonamide

3-Methylamino-propionic acid methyl ester

Methyl acrylate (10 g, 116 mmol) is dissolved in methanol (20 mL) andcooled to −20° C. Methylamine (2 M in tetrahydrofuran, 90 mL, 180 mmol)is added via addition funnel and the reaction is allowed to stir at −20°C. for 2 hours. Solvents were then removed in vacuo and the residue isdistilled under reduced pressure (45° C. at 5 torr) to afford the titlecompound as a colorless liquid (3.5 g, 28% yield). ¹H NMR (CDCl₃) δ 2.44(s, 3H), 2.52 (t, 2H, J=6.31 Hz), 2.86 (t, 2H, J=6.31 Hz), 3.69 (s, 3H).

1-Methyl-1,3,4,9-tetrahydro-indeno[2,1-b]pyridin-2-one

3-Methylamino-propionic acid methyl ester (1.5 g, 13.64 mmol) is addedto a solution of 2-indanone (1.7 g, 12.86 mmol) in toluene (20 mL) andthe reaction is brought to reflux for 2.5 hours. Toluene is removed invacuo and the residue is dissolved in ethylene glycol (17 mL) and theresulting solution is heated to reflux for 8 hours. The reaction isallowed to cool to ambient temperature, is poured over water andextracted with dichloromethane. The organic phase is dried overmagnesium sulfate and concentrated in vacuo to afford the crude titlecompound as a brown oil. The crude product is purified by silica gelchromatography (gradient of ethyl acetate in hexanes 10-100%) affording720 mg (28% yield) of the title compound. ¹H NMR (CDCl₃) δ2.70-2.80 (m,4H), 3.23 (s, 3H), 3.5 (s, 2H), 7.07-7.15 (m, 2H), 7.24-7.33 (m, 1H),7.38 (d, 1H, J=7.07). MS (m/z): 199.2 (M+1).

2-Chloro-5-(1-methyl-2-oxo-2,3,4,9-tetrahydro-1H-indeno[2,1-b]pyridine-7-carbonyl)-benzenesulfonamide

Under nitrogen, aluminum chloride (2.0 g, 15.06 mmol) is slurried indichloromethane (100 mL) then 4-chloro-3-sulfamoyl-benzoyl chloride(1.28 g, 5.02 mmol) is added and allowed to stir at ambient temperaturefor 30 minutes. To this mixture1-methyl-1,3,4,9-tetrahydro-indeno[2,1-b]pyridin-2-one (1.0 g, 5.02mmol) is added in 13 mL dichloromethane. The reaction is allowed to stirat ambient temperature for 1 hour. The reaction mixture is poured overice-water (300 mL) and extracted with dichloromethane, organic separatedand concentrated to give crude title compound. Recrystallization fromwarm methanol afforded the title compound as a yellow powder (1.11 g,53% yield). ¹H NMR (MeOD) δ 2.77-2.83 (m, 4H), 3.28 (s, 3H), 3.59 (s,2H), 5.17 (s, 2H), 7.19 (d, 1H, J=7.83 Hz), 7.68-7.73 (m, 2H), 7.86 (s,1H), 7.94 (dd, 1H, J=2.27, 8.33 Hz), 8.46 (d, 1H, J=2.02 Hz). MS (m/z):417 (M+1). M.P. 259-260° C.

Example 392-Chloro-5-(1-ethyl-2-oxo-2,3,4,9-tetrahydro-1H-indeno[2,1-b]pyridine-7-carbonyl)-benzenesulfonamide

3-Ethylamino-propionic acid methyl ester

Methyl acrylate (5.22 g, 60.6 mmol) is dissolved in methanol (20 mL) andcooled to −20° C. Ethylamine (2 M in tetrahydrofuran, 47 mL, 94 mmol) isadded via addition funnel and the reaction is allowed to stir at −20° C.for 2 hours. Solvents were then removed in vacuo and the residue isdistilled under reduced pressure to afford the title compound as acolorless liquid (2.41 g, 30% yield). ¹H NMR (CDCl₃) δ 1.11 (t, 3H,J=7.02 Hz), 2.53 (t, 2H, J=6.58 Hz), 2.66 (q, 2H, J=7.02 Hz), 2.89 (t,2H, J=6.58 Hz), 3.69 (s, 3H).

1-Ethyl-1,3,4,9-tetrahydro-indeno[2,1-b]pyridin-2-one

3-Ethylamino-propionic acid methyl ester (2.41 g, 18.4 mmol) is added toa solution of 2-indanone (2.3 g, 17.33 mmol) in toluene (27 mL), and thereaction is brought to reflux for 2 hours. Toluene is removed in vacuoand the residue is dissolved in ethylene glycol (23 mL) and theresulting solution is heated to reflux for 8 hours. The reaction isallowed to cool to ambient temperature and is poured over water andextracted with dichloromethane. The organic phase is dried overmagnesium sulfate and concentrated in vacuo to afford the crude titlecompound. The crude product is purified by silica gel chromatography(gradient of ethyl acetate in hexanes 10-100%) affording 1 g (27% yield)of the title compound. MS (m/z): 213.3 (M+1).

2-Chloro-5-(1-ethyl-2-oxo-2,3,4,9-tetrahydro-1H-indeno[2,1-b]pyridine-7-carbonyl)-benzenesulfonamide

Under nitrogen, aluminum chloride (0.7 g, 4.9 mmol) is slurried indichloromethane (15 mL) then 4-chloro-3-sulfamoyl-benzoyl chloride (287mg, 1.13 mmol) is added and allowed to stir at ambient temperature for30 minutes. Then 1-ethyl-1,3,4,9-tetrahydro-indeno[2,1-b]pyridin-2-one(240 mg, 1.13 mmol) is added in 4 mL dichloromethane. The reaction isallowed to stir at ambient temperature for 1.5 hours. The reactionmixture is poured over ice-water and extracted with dichloromethane, theorganic layer is separated and concentrated to give crude title compoundas a brown oil. Recrystallization from warm dichloromethane afforded thetitle compound as a yellow powder (125 mg, 26% yield). ¹H NMR (MeOD) δ1.26 (t, 2H, J=7.01 Hz), 2.76-2.83 (m, 4H), 3.6 (s, 2H), 3.77 (q, 2H,J=7.01), 5.19 (s, 2H), 7.19 (d, 1H, J=8.11 Hz), 7.68-7.73 (m, 2H), 7.86(d, 1H, J=1.09), 7.94 (dd, 1H, J=2.19, 8.11 Hz), 8.46 (d, 1H, J=1.97Hz). MS (m/z): 431 (M+1).

Example 402-Chloro-5-[4-(2,5-dimethyl-pyrrol-1-yl)-3-fluoro-benzoyl]-benzenesulfonamide

Following method B,2-chloro-5-((4-(2,5-dimethyl-pyrrol-1-yl)-3-fluoro-phenyl)-hydroxy-methyl)-benzenesulfonamideis synthesized from the corresponding aryl bromide. In the next step, asolution of 100 mg of2-chloro-5-((4-(2,5-dimethyl-pyrrol-1-yl)-3-fluoro-phenyl)-hydroxy-methyl)-benzenesulfonamide(0.24 mmol, 1 equivalent), 43 mg of 4-methylmorpholine N-oxide, and 122mg of 4 Å molecular sieves in 5 mL of dichloromethane is stirred at roomtemperature as 5 mg of tetrapropylammonium perruthenate is added. Thereaction is stirred at room temperature for 1 h, then filtered through apad of silica gel, eluted with ethyl acetate and concentrated in vacuo.After purification by flash chromatography, 45 mg of product isobtained. ¹H NMR (400 MHz, CDCl₃): δ 2.05 (s, 6H), 5.20 (s, 2H), 6.0 (s,2H), 7.40 (t, 1H, J=8 Hz), 7.65-7.75 (m, 3H), 8.05 (dd, 1H, J=8 Hz),8.55 (d, 1H, J=2 Hz). MS (m/z): 407 (M+1).

Example 41 2-Chloro-5-(1H-indole-6-carbonyl)-benzenesulfonamide

A dispersion of potassium hydride in oil (33.15 mmol) is washed withhexanes under argon then tetrahydrofuran (310 mL) is added at 0° C. andthe resulting suspension is treated by dropwise addition of 6.77 g of6-bromoindole in tetrahydrofuran (61 mL). The reaction mixture isstirred at 0° C. for 15 min to give a yellow solution. A solution of44.2 mL of tert-butyllithium (1.5 M in pentane) is added slowly at −78°C. while maintaining the temperature below −75° C. to produce a yellowsuspension. After 15 min a solution of 3.08 g of4-chloro-N-methoxy-N-methyl-3-sulfamoyl-benzamide in tetrahydrofuran (61mL) is added and the temperature is allowed to increase slowly to 0° C.The reaction mixture is quenched by addition of 62 mL of saturatedaqueous ammonium chloride and extracted with ethyl ether. The organicswere washed with water, dried over magnesium sulfate and concentrated to9.65 g of a brown oil which is chromatographed on silica gel (1:1hexanes/ethyl acetate) to give2-chloro-5-(1H-indole-6-carbonyl)-benzenesulfonamide as a yellow foam.MS (m/z): 333 (M−1); Rf 0.37 (1:1 hexanes/ethyl acetate).

Example 42 2-Fluoro-5-(1H-indole-6-carbonyl)-benzenesulfonamide

A solution of 0.997 g of 6-bromoindole in tetrahydrofuran (20 mL) iscooled to −50° C. and treated by slow addition of 8.79 mL oftert-butyllithium (1.5 M in pentane). After 2 h at −50° C. the reactionmixture is treated with 0.4 g of4-fluoro-N-methoxy-N-methyl-3-sulfamoyl-benzamide in tetrahydrofuran (10mL), stirred for an additional 3 h at −50° C. and quenched by additionof 2 mL of saturated aqueous ammonium chloride. The reaction mixture istaken up in ethyl acetate, washed with a saturated sodium chloridesolution and dried (magnesium sulfate). After concentration in vacuo theresidue is purified by silica gel chromatography (1:1 hexanes/ethylacetate) to give 2-fluoro-5-(1H-indole-6-carbonyl)-benzenesulfonamide asan amorphous solid. MS (m/z): 317 (M−1); Rf 0.32 (1:1 hexanes/ethylacetate).

Example 43 5-(1H-Indole-6-carbonyl)-2-methyl-benzenesulfonamide

5-(1H-Indole-6-carbonyl)-2-methyl-benzenesulfonamide is prepared from 4g of N-methoxy-4,N-dimethyl-3-sulfamoyl-benzamide according to theprocedure described in Method C. MS (m/z): 313 (M−1); Rf 0.28 (1:1hexanes/ethyl acetate).

Preparation of N-methoxy-4,N-dimethyl-3-sulfamoyl-benzamide

A mixture of 3.63 g of 4-methyl-3-sulfamoyl-benzoic acid, 1.92 g ofN,O-dimethylhydroxylamine hydrochloride, and 5.02 mL of triethylamine inmethylene chloride (120 mL) is treated with 8.32 g ofbenzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate. The reaction mixture is stirred overnight at roomtemperature, washed sequentially with saturated aqueous sodiumbicarbonate, water and a saturated sodium chloride solution, dried(magnesium sulfate) and concentrated in vacuo. The crude material ispurified by silica gel chromatography (1:2 hexanes/ethyl acetate) togive N-methoxy-4,N-dimethyl-3-sulfamoyl-benzamide as a white powder. MS(m/z): 257 (M−1); Rf 0.25 (1:2 hexanes/ethyl acetate).

Example 44 3-(1H-Indole-6-carbonyl)-benzenesulfonamide

3-(1H-Indole-6-carbonyl)-benzenesulfonamide is prepared from 2.95 g ofN-methoxy-N-methyl-3-sulfamoyl-benzamide according to the proceduredescribed in method C. MS (m/z): 299 (M−1); Rf 0.25 (1:1 hexanes/ethylacetate).

Preparation of N-methoxy-N-methyl-3-sulfamoyl-benzamide

N-Methoxy-N-methyl-3-sulfamoyl-benzamide is prepared from 3.14 g of3-sulfamoyl-benzoic acid according to the procedure described in methodC. MS (m/z): 243 (M−1); Rf 0.21 (1:2 hexanes/ethyl acetate).

Preparation of 4-fluoro-N-methoxy-N-methyl-3-sulfamoyl-benzamide

4-Fluoro-N-methoxy-N-methyl-3-sulfamoyl-benzamide is prepared from 0.5 gof 4-fluoro-3-sulfamoyl-benzoic acid according to the proceduredescribed in method C. MS (m/z): 261 (M−1); Rf 0.45 (9:1 methylenechloride/methanol).

Example 45 2-chloro-5-(3-phenyl-1H-indole-6-carbonyl)-benzenesulfonamide

Method for the Preparation of5-[3-bromo-1-(tert-butyldimethylsilyl)-1H-indole-6-carbonyl]-2-chloro-N-(tert-butyldimethylsilyl)-benzenesulfonamideStep 1:

A solution of 3.89 g of2-chloro-5-(1H-indole-6-carbonyl)-benzenesulfonamide in tetrahydrofuran(370 mL) is cooled to −78° C. and treated by dropwise addition ofn-butyllithium in hexane (1.6 M, 24.4 mL). After 15 min at −78° C. theorange solution is treated by addition of 3.47 g oftert-butyldimethylchlorosilane in tetrahydrofuran (50 mL) and thetemperature is allowed to increase slowly to 0° C. After 1.5 h at 0° C.the reaction mixture is treated with water at 0° C. and extracted withdiethyl ether. The organic phase is washed with a saturated sodiumchloride solution, dried (magnesium sulfate) and concentrated to an oilwhich is triturated under sonication in diisopropylether to give5-[1-(tert-butyldimethylsilyl)-1H-indole-6-carbonyl]-2-chloro-N-(tert-butyldimethylsilyl)-benzenesulfonamideas a white powder. MS (m/z): 563 (M+1), Rf 0.60 (2:1 hexanes/ethylacetate).

Step 2:

A solution of 1.7 g of5-[1-(tert-butyldimethylsilyl)-1H-indole-6-carbonyl]-2-chloro-N-(tert-butyldimethylsilyl)-benzenesulfonamidein tetrahydrofuran (110 mL) at −78° C. is treated with 0.564 g ofN-bromosuccinimide. After 6 h at −78° C. the temperature is allowed toreach room temperature. The reaction mixture is taken up in diethylether, washed with water and dried (magnesium sulfate). The solvent isevaporated and the residue is triturated under sonication withdiisopropylether to give5-[3-bromo-1-(tert-butyldimethylsilyl)-1H-indole-6-carbonyl]-2-chloro-N-(tert-butyldimethylsilyl)-benzenesulfonamideas a tan powder. MS (m/z): 643 (M+1); Rf 0.90 (95:5 methylenechloride/methanol).

2-chloro-5-(3-phenyl-1H-indole-6-carbonyl)-benzenesulfonamide

To a mixture of 0.1 g of5-[3-bromo-1-(tert-butyl-dimethyl-silyl)-1H-indole-6-carbonyl]-2-chloro-N-(tert-butyl-dimethyl-silyl)-benzenesulfonamide,0.039 g of phenylboronic acid and 0.025 g of1,1′-bis(diphenylphosphino)-ferrocenedichloropalladium(II)-dichloromethanecomplex in dimethoxyethane (3.6 mL) is added 0.099 g of tri-potassiumphosphate in water (1.2 mL). The solution is heated to 130° C. for 5minutes (microwave irradiation). The reaction mixture is extracted withethyl acetate. The organic phase is washed with water, dried (magnesiumsulfate) and concentrated to 0.094 g of crude product. Purification viaflash chromatography on silica gel (98:2 methylene chloride/methanol)afforded 2-chloro-5-(3-phenyl-1H-indole-6-carbonyl)-benzenesulfonamideas a tan powder. MS (m/z): 409 (M−1); Rf 0.22 (95:5:0.5 methylenechloride/methanol/ammonium hydroxide).

Likewise the following compounds are prepared from5-[3-bromo-1-(tert-butyl-dimethyl-silyl)-1H-indole-6-carbonyl]-2-chloro-N-(tert-butyl-dimethyl-silyl)-benzenesulfonamide.

2-Chloro-5-[3-(4-methoxy-phenyl)-1H-indole-6-carbonyl]-benzenesulfonamide

MS (m/z): 439 (M−1); Rf 0.22 (95:5 methylene chloride/methanol).

2-Chloro-5-[3-(4-fluoro-phenyl)-1H-indole-6-carbonyl]-benzenesulfonamide

MS (m/z): 427 (M−1); Rf 0.16 (3:1 methylene chloride/diethyl ether).

5-[3-(3-Acetyl-phenyl)-1H-indole-6-carbonyl]-2-chloro-benzenesulfonamide

MS (m/z): 452 (M−1); Rf 0.18 (3:1 methylene chloride/diethyl ether).

5-[3-(4-Acetyl-phenyl)-1H-indole-6-carbonyl]-2-chloro-benzenesulfonamide

MS (m/z): 451 (M−1); Rf 0.16 (3:1 methylene chloride/diethyl ether).

2-Chloro-5-[3-(3-methanesulfonyl-phenyl)-1H-indole-6-carbonyl]-benzenesulfonamide

MS (m/z): 487 (M−1); Rf 0.11 (1:1 methylene chloride/diethyl ether).

2-Chloro-5-[3-(4-methanesulfonyl-phenyl)-1H-indole-6-carbonyl]-benzenesulfonamide

MS (m/z): 487 (M−1); Rf 0.09 (2:1 methylene chloride/diethyl ether).

2-Chloro-5-[3-(4-ethanesulfonyl-phenyl)-1H-indole-6-carbonyl]-benzenesulfonamide

MS (m/z): 501 (M−1); Rf 0.12 (3:1 methylene chloride/diethyl ether).

5-(3-Biphenyl-4-yl-1H-indole-6-carbonyl)-2-chloro-benzenesulfonamide

MS (m/z): 485 (M−1); Rf 0.19 (95:5:0.5 methylenechloride/methanol/ammonium hydroxide).

2-Chloro-5-(3-thiophen-3-yl-1H-indole-6-carbonyl)-benzenesulfonamide

MS (m/z): 415 (M−1); Rf 0.23 (3:1 methylene chloride/diethyl ether).

5-[3-(5-Acetyl-thiophen-2-yl)-1H-indole-6-carbonyl]-2-chloro-benzenesulfonamide

MS (m/z): 451 (M−1); Rf 0.16 (3:1 methylene chloride/diethyl ether).

5-(1H,1′H-[3,5′]Biindolyl-6-carbonyl)-2-chloro-benzenesulfonamide

MS (m/z): 447 (M−1); Rf 0.22 (3:1 methylene chloride/diethyl ether).

2-Chloro-5-(3-pyridin-3-yl-1H-indole-6-carbonyl)-benzenesulfonamide

MS (m/z): 410 (M−1); Rf 0.23 (90:10:1 methylenechloride/methanol/ammonium hydroxide).

2-Chloro-5-(3-pyrimidin-5-yl-1H-indole-6-carbonyl)-benzenesulfonamide

MS (m/z): 411 (M−1); Rf 0.08 (95:5:0.5 methylenechloride/methanol/ammonium hydroxide).

2-Chloro-5-{3-[4-(morpholine-4-carbonyl)-phenyl]-1H-indole-6-carbonyl}-benzenesulfonamide

MS (m/z): 522 (M−1); Rf 0.12 (95:5 methylene chloride/methanol).

2-Chloro-5-[3-(3,5-dimethyl-isoxazol-4-yl)-1H-indole-6-carbonyl]-benzenesulfonamide

MS (m/z): 428 (M−1); Rf 0.13 (3:1 methylene chloride/diethyl ether).

2-Chloro-5-[3-(5-chloro-2-methoxy-pyridin-4-yl)-1H-indole-6-carbonyl]-benzenesulfonamide

MS (m/z): 474 (M−1); Rf 0.21 (3:1 methylene chloride/diethyl ether).

2-Chloro-5-(3-pyridin-4-yl-1H-indole-6-carbonyl)-benzenesulfonamide

MS (m/z): 410 (M−1); Rf 0.26 (90:10:1 methylenechloride/methanol/ammonium hydroxide).

2-Chloro-5-[3-(2-chloro-pyridin-4-yl)-1H-indole-6-carbonyl]-benzenesulfonamide

MS (m/z): 444 (M−1); Rf 0.08 (95:5:0.5 methylenechloride/methanol/ammonium hydroxide).

Example 462-Chloro-5-[3-(2-methyl-pyridin-4-yl)-1H-indole-6-carbonyl]-benzenesulfonamide

To a mixture of 0.1 g of5-[3-bromo-1-(tert-butyl-dimethyl-silyl)-1H-indole-6-carbonyl]-2-chloro-N-(tert-butyl-dimethyl-silyl)-benzenesulfonamide,0.095 g of crude (2-methyl-4-pyridinyl)-boronic acid and 0.025 g of1,1′-bis(diphenylphosphino)-ferrocenedichloropalladium(II)-dichloromethanecomplex in dimethoxyethane (3.6 mL) is added 0.099 g of tri-potassiumphosphate in water (1.2 mL). The solution is heated to 130° C. for 5minutes (microwave irradiation). The reaction mixture is extracted withethyl acetate. The organic phase is washed with water, dried overmagnesium sulfate and concentrated to 0.071 g of crude product.Purification via flash chromatography on silica gel (95:5:0.5 methylenechloride/methanol/ammonium hydroxide) afforded2-chloro-5-[3-(2-methyl-pyridin-4-yl)-1H-indole-6-carbonyl]-benzenesulfonamideas a tan powder. MS (m/z): 424 (M−1); Rf 0.06 (95:5:0.5 methylenechloride/methanol/ammonium hydroxide).

Preparation of (2-methyl-4-pyridinyl)-boronic acid Step 1:

A suspension of 10 g of 4-bromopyridine hydrochloride in tetrahydrofuran(180 mL) is treated at −78° C. with 48.2 mL of methylmagnesium chloride(3 M in tetrahydrofuran). After 25 min at −78° C. the reaction mixtureis treated by slow addition of a solution of 7.69 mL of phenylchloroformate in tetrahydrofuran (20 mL) resulting in an increase of thereaction temperature to room temperature. The reaction mixture isstirred at room temperature for 10 min and then treated by addition of asaturated aqueous solution of ammonium chloride (84 mL) at 0° C.followed by diethyl ether. The organic phase is washed with water, 2 Naqueous HCl, water and a saturated sodium chloride solution, dried overmagnesium sulfate and concentrated in vacuo to 17.1 g of carbamate as anorange oil. This material is taken up in toluene (200 mL) and treatedwith a solution of 15.64 g of o-chloranil in acetic acid (117 mL). After26 h at room temperature the resulting solution is treated with 30%aqueous sodium hydroxide. The resulting emulsion is filtered throughCelite. Phases are separated and extracted with toluene. The organicsare washed with water and extracted with 2 N HCl. Acidic extracts arewashed with diethyl ether, treated with 30% aqueous sodium hydroxide at0° C. and extracted with methylene chloride. The organic extracts aredried (magnesium sulfate), concentrated and purified by silica gelchromatography (1:1 methylene chloride/diethyl ether) to give4-bromo-2-methyl-pyridine as an oil. MS (m/z): 174 (M+1); Rf 0.31 (1:1methylene chloride/diethyl ether).

Step 2:

A solution of 4.7 mL of n-butyllithium (1.6 M in hexane) in diethylether (20 mL) is cooled to −78° C. and treated with a solution of 1.07 gof 4-bromo-2-methyl-pyridine in diethyl ether (10 mL) previously driedover molecular sieves at 40° C. overnight. After 20 min at −78° C. theresulting orange suspension is treated with 1.87 mL oftriisopropylborate and the temperature is allowed to increase to roomtemperature over a 2 h period. After an additional 2 h the reactionmixture is treated with water. The organic phase is extracted with 0.5 Nsodium hydroxide. Extracts are washed with diethyl ether and acidifiedwith 2 N HCl to pH 6. The resulting suspension is concentrated undervacuum to give a paste containing (2-methyl-4-pyridinyl)-boronic acidwhich is used without further purification for the Suzuki coupling. MS(m/z): 136 (M−1).

Likewise the following compounds are prepared from5-[3-bromo-1-(tert-butyl-dimethyl-silyl)-1H-indole-6-carbonyl]-2-chloro-N-(tert-butyl-dimethyl-silyl)-benzenesulfonamideand the corresponding boronic acids

2-Chloro-5-[3-(2-ethyl-pyridin-4-yl)-1H-indole-6-carbonyl]-benzenesulfonamide

MS (m/z): 438 (M−1); Rf 0.10 (95:5:0.5 methylenechloride/methanol/ammonium hydroxide).

Preparation of (2-ethyl-4-pyridinyl)-boronic acid

(2-Ethyl-4-pyridinyl)-boronic acid is prepared from 5 g of4-bromopyridine hydrochloride according to the procedure described inexample 46, step 1 and step 2. MS (m/z): 150 (M−1).

2-Chloro-5-[3-(2-cyclopropyl-pyridin-4-yl)-1H-indole-6-carbonyl]-benzenesulfonamide

MS (m/z): 450 (M−1); Rf 0.13 (95:5:0.5 methylenechloride/methanol/ammonium hydroxide).

(2-cyclopropyl-4-pyridinyl)-boronic acid

(2-Cyclopropyl-4-pyridinyl)-boronic acid is prepared from 5 g of4-bromopyridine hydrochloride according to the procedure described inexample 46, step 1 and step 2. MS (m/z): 162 (M−1).

2-Chloro-5-{3-[2-(3-methoxy-propyl)-pyridin-4-yl]-1H-indole-6-carbonyl}-benzenesulfonamide

MS (m/z): 482 (M−1); Rf 0.07 (95:5:0.5 methylenechloride/methanol/ammonium hydroxide).

[2-(3-methoxy-propyl)-4-pyridinyl]-boronic acid

[2-(3-Methoxy-propyl)-4-pyridinyl]-boronic acid is prepared from 1.35 gof 4-bromopyridine hydrochloride according to the procedure described inexample 46, step 1 and step 2. MS (m/z): 196 (M+1).

2-Chloro-5-{3-[2-(3-morpholin-4-yl-propyl)-pyridin-4-yl]-1H-indole-6-carbonyl}-benzenesulfonamide

MS (m/z): 539 (M+1); Rf 0.15 (90:10:1 ethyl acetate/methanol/ammoniumhydroxide).

[2-(3-morpholin-4-yl-propyl)-4-pyridinyl]-boronic acid

[2-(3-morpholin-4-yl-propyl)-4-pyridinyl]-boronic acid is prepared from5.36 g of 4-bromopyridine hydrochloride according to the proceduredescribed in example 46, step 1 and step 2. MS (m/z): 251 (M+1).

2-Chloro-5-{3-[2-(2-dimethylamino-ethoxy)-pyridin-4-yl]-1H-indole-6-carbonyl}-benzenesulfonamide

MS (m/z): 497 (M−1); Rf 0.2 (90:10:1 ethyl acetate/methanol/ammoniumhydroxide).

Example 47 Preparation of[2-(2-dimethylamino-ethoxy)-4-pyridinyl]-boronic acid Step 1:

A mixture of 5.55 g of sodium and 26.9 mL of 2-dimethylaminoethanol intetrahydrofuran (180 mL) is heated to reflux for 20 hours. The reactionmixture is cooled to room temperature, treated with 4 g of4-amino-2-chloropyridine and heated to 140° C. for 20 min (microwaveirradiation). The reaction mixture is treated with concentrated HCl topH 8 at 0° C., saturated with sodium chloride and extracted with diethylether. The organics are dried (magnesium sulfate) and concentrated to11.9 g of crude product which is purified by silica gel chromatography(90:10:1 ethyl acetate/methanol/ammonium hydroxide) to give2-(2-dimethylamino-ethoxy)-pyridin-4-ylamine as tan crystals. MS (m/z):182 (M+1); Rf 0.1 (90:10:1 ethyl acetate/methanol/ammonium hydroxide).

Step 2:

A mixture of 1.2 g of 2-(2-dimethylamino-ethoxy)-pyridin-4-ylamine,0.749 g of sodium bromide and 1.16 g of copper sulfate is cooled to 0°C. and treated with 12 mL of 9 M sulfuric acid with stirring. Theresulting dark suspension is treated at 0° C. with a solution of 0.503 gof sodium nitrite in water (0.8 mL) and stirred at 0° C. for 1.5 h andat room temperature for 1.5 h. The reaction mixture is pored ontoice-water, brought to basic pH with 30% sodium hydroxide, and extractedwith methylene chloride. The organics are dried (magnesium sulfate),concentrated and purified by silica gel chromatography (7:3 ethylacetate/methanol) to give[2-(4-bromo-pyridin-2-yloxy)-ethyl]-dimethyl-amine as an oil. MS (m/z):245 (M+1); Rf 0.25 (7:3 ethyl acetate/methanol).

Step 3:

[2-(2-Dimethylamino-ethoxy)-4-pyridinyl]-boronic acid is prepared from0.713 g of [2-(4-bromo-pyridin-2-yloxy)-ethyl]-dimethyl-amine accordingto the procedure described in Example 6 step 2. MS (m/z): 211 (M+1).

The following compound can be prepared with similar steps.

2-Chloro-5-{3-[2-(2-morpholin-4-yl-ethoxy)-pyridin-4-yl]-1H-indole-6-carbonyl}-benzenesulfonamide

MS (m/z): 539 (M−1); Rf 0.38 (90:10:1 ethyl acetate/methanol/ammoniumhydroxide).

Preparation of [2-(2-morpholin-4-yl-ethoxy)-4-pyridinyl]-boronic acid

[2-(2-Morpholin-4-yl-ethoxy)-4-pyridinyl]-boronic acid is prepared fromN-(2-hydroxyethyl)-morpholine according to the procedure described forthe preparation of [2-(2-dimethylamino-ethoxy)-4-pyridinyl]-boronicacid. MS (m/z): 253 (M+1).

Example 482-Methyl-5-[3-(2-methyl-pyridin-4-yl)-1H-indole-6-carbonyl]-benzenesulfonamide

2-Methyl-5-[3-(2-methyl-pyridin-4-yl)-1H-indole-6-carbonyl]-benzenesulfonamideis prepared from 0.25 g of5-[3-bromo-1-(tert-butyl-dimethyl-silyl)-1H-indole-6-carbonyl]-N-(tert-butyl-dimethyl-silyl)-2-methyl-benzenesulfonamideaccording to the procedure described in Example 6 (microwave irradiationat 150° C. for 5 min). MS (m/z): 404 (M−1); Rf 0.19 (90:10:1 methylenechloride/methanol/ammonium hydroxide).

Preparation of5-[3-bromo-1-(tert-butyl-dimethyl-silyl)-1H-indole-6-carbonyl]-N-(tert-butyl-dimethyl-silyl)-2-methyl-benzenesulfonamideStep 1:

5-[1-(tert-Butyldimethylsilyl)-1H-indole-6-carbonyl]-N-(tert-butyldimethylsilyl)-2-methyl-benzenesulfonamideis prepared from 3.09 g of5-(1H-indole-6-carbonyl)-2-methyl-benzenesulfonamide according to theprocedure described in Example 5, step 1. MS (m/z): 543 (M+1); Rf 0.75(2:1 hexanes/ethyl acetate).

Step 2:

5-[3-Bromo-1-(tert-butyldimethylsilyl)-1H-indole-6-carbonyl]-N-(tert-butyldimethylsilyl)-2-methyl-benzenesulfonamideis prepared from 3.21 g of5-[1-(tert-butyldimethylsilyl)-1H-indole-6-carbonyl]-N-(tert-butyldimethylsilyl)-2-methyl-benzenesulfonamideaccording to the procedure described in Example 5, step 2. MS (m/z): 622(M+1); Rf 0.77 (95:5 methylene chloride/methanol).

Example 493-[3-(2-Methyl-pyridin-4-yl)-1H-indole-6-carbonyl]-benzenesulfonamide

3-[3-(2-Methyl-pyridin-4-yl)-1H-indole-6-carbonyl]-benzenesulfonamide isprepared from 0.25 g of5-[3-bromo-1-(tert-butyl-dimethyl-silyl)-1H-indole-6-carbonyl]-N-(tert-butyl-dimethyl-silyl)-benzenesulfonamideaccording to the procedure described in Example 6 (microwave irradiationat 150° C. for 5 min). MS (m/z): 390 (M−1); Rf 0.19 (90:10:1 methylenechloride/methanol/ammonium hydroxide)

Preparation of5-[3-bromo-1-(tert-butyl-dimethyl-silyl)-1H-indole-6-carbonyl]-N-(tert-butyl-dimethyl-silyl)-benzenesulfonamideStep 1:

5-[1-(tert-Butyldimethylsilyl)-1H-indole-6-carbonyl]-N-(tert-butyldimethylsilyl)-benzenesulfonamideis prepared from 1.857 g of 3-(1H-indole-6-carbonyl)-benzenesulfonamideaccording to the procedure described in example 45, step 1. MS (m/z):529 (M+1); Rf 0.66 (2:1 hexanes/ethyl acetate).

Step 2:

5-[3-Bromo-1-(tert-butyldimethylsilyl)-1H-indole-6-carbonyl]-N-(tert-butyldimethylsilyl)-benzenesulfonamideis prepared from 1.14 g of5-[1-(tert-butyldimethylsilyl)-1H-indole-6-carbonyl]-N-(tert-butyldimethylsilyl)-benzenesulfonamideaccording to the procedure described in example 45, step 2. MS (m/z):607 (M+1); Rf 0.78 (95:5 methylene chloride/methanol).

Likewise the following compounds are prepared from5-[3-bromo-1-(tert-butyl-dimethyl-silyl)-1H-indole-6-carbonyl]-N-(tert-butyl-dimethyl-silyl)-benzenesulfonamideand the corresponding boronic acids.

3-{3-[2-(3-Methoxy-propyl)-pyridin-4-yl]-1H-indole-6-carbonyl}-benzenesulfonamide

MS (m/z): 450 (M+1); Rf 0.22 (90:10:1 methylenechloride/methanol/ammonium hydroxide).

3-{3-[2-(3-Methoxy-propyl)-pyridin-4-yl]-1H-indole-6-carbonyl}-benzenesulfonamide

MS (m/z): 505 (M+1); Rf 0.10 (90:10:1 methylenechloride/methanol/ammonium hydroxide).

Example 50

The following compounds were prepared following method A using aluminumtrichloride or other suitable aluminum reagents and the appropriatesubstituted phenyl moiety as illustrated by the following procedure.

5-Benzoyl-2-chloro-benzenesulfonamide

To a well stirred solution of 4-chloro-3-sulfamoyl-benzoyl chloride (0.5g, 1.97 mmol) in 5 mL methylene chloride is added aluminum chloride(0.485 g, 1.85 mmol). After 30 min, benzene (1 mL, 5.72 mmol) is addedand the reaction is stirred for 2 h at room temperature. The reactionmixture is then poured over ice, acidified with 6 N HCl and extractedthree times with diethyl ether. The organic layers were combined, driedwith magnesium sulfate, filtered and concentrated in vacuo. Theresulting residue is purified via silica gel chromatography to yield 40mg (69%) of the title compound as a tan solid. MS (m/z): 294 (M-1).Analytics calculated for C₁₃H₁₀ClNO₃S: C, 52.8; H, 3.41; N, 4.74. Found:C, 52.62; H, 3.21; N, 4.72.

2-Chloro-5-(4′-ethyl-biphenyl-4-carbonyl)-benzenesulfonamide

MS (m/z): 310 (M−1). Analytics calculated for C₁₃H₁₀ClNO₄S: C, 50.09; H,3.23; N, 4.49. Found: C, 49.91; H, 3.18; N, 4.44.

2-Chloro-5-(4′-allyloxy-benzoyl)-benzenesulfonamide

MS (M−1) 350.

5-(4-Bromo-benzoyl)-2-chloro-benzenesulfonamide

MS (m/z): 448 (M−1). Analytics calculated for C₁₃H₉BrClNO₃S: C, 41.68;H, 2.42; N, 3.74. Found: C, 41.69; H, 1.99; N, 3.56.

5-(4-tert-Butyl-benzoyl)-2-chloro-benzenesulfonamide

MS (m/z): 352 (M+1).

2-Chloro-5-(4-cyclopropyl-benzoyl)-benzenesulfonamide

MS (m/z): 334 (M−1). Analytics calculated for C₁₆H₁₄ClNO₃S: C, 57.23; H,4.2; N, 4.17. Found: C, 56.69; H, 4.13; N, 4.01.

2-Chloro-5-(4-cyclopentyl-benzoyl)-benzenesulfonamide

MS (m/z): 364 (M+1). Analytics calculated for C₁₈H₁₈ClNO₃S: C, 59.42; H,4.99; N, 3.85. Found: C, 59.28; H, 4.76; N, 3.83.

2-Chloro-5-(4-cyclohexyl-benzoyl)-benzenesulfonamide

¹H NMR (400 MHz, DMSO): δ 1.3-1.8 (m, 10H), 2.6-2.7 (br, 1H), 7.4 (d,2H, J=8 Hz), 7.70 (d, 2H, J=8 Hz), 7.80 (m, 3H), 7.88-7.92 (m, 1H), 8.28(d, 1H, J=2 Hz). MS (m/z): 376 (M−1). Analytics calculated forC₁₉H₂₀ClNO₃S: C, 60.39; H, 5.33; N, 3.71. Found: C, 60.53; H, 5.08; N,3.46.

2-Chloro-5-(4-cyano-benzoyl)-benzenesulfonamide

¹H NMR (400 MHz, CDCl₃): δ 5.3 (br, 2H), 7.75 (d, 1H, J=8 Hz), 7.8-7.9(m, 4H), 7.97 (m, 1H), 8.45 (d, 1H, J=2 Hz). MS (m/z): 319 (M−1).

5-(2-Bromo-4-methyl-benzoyl)-2-chloro-benzenesulfonamide

MS (m/z): 386 (M−1). Analytics calculated for C₁₄H₁₁BrClNO₃S: C, 43.26;H, 2.85; N, 3.6. Found: C, 43.19; H, 2.83; N, 3.60.

5-(4-Bromo-2-methyl-benzoyl)-2-chloro-benzenesulfonamide

MS (m/z): 386 (M−1). Analytics calculated for C₁₄H₁₁BrClNO₃S: C, 43.26;H, 2.85; N, 3.6. Found: C, 43.07; H, 2.86; N, 3.60.

2-Chloro-5-(2-fluoro-4-methoxy-benzoyl)-benzenesulfonamide

MS (m/z): 342 (M−1).

2-Chloro-5-(3-fluoro-4-hydroxy-benzoyl)-benzenesulfonamide

MS (m/z): 330 (M+1). Analytics calculated for C₁₃H₉ClFNO₄S: C, 47.35; H,2.75; N, 4.25. Found: C, 47.47; H, 2.67; N, 4.07. M.P. 206-208° C.

2-Chloro-5-(2,4-dimethoxy-benzoyl)-benzenesulfonamide

MS (m/z): 356 (M+1). Analytics calculated for C₁₅H₁₄ClNO₅S: C, 50.64; H,3.97; N, 3.94. Found: C, 50.49; H, 3.72; N, 3.91.

2-Chloro-5-(2-fluoro-4-hydroxy-benzoyl)-benzenesulfonamide

MS (m/z): 330 (M+1). Analytics calculated for C₁₃H₉ClFNO₄S: C, 47.35; H,2.75; N, 4.25. Found: C, 47.36; H, 2.65; N, 3.99. M.P. 183-185° C.

5-(Biphenyl-4-carbonyl)-2-chloro-benzenesulfonamide

MS (m/z): 370 (M−1).

2-Chloro-5-(4′-methyl-biphenyl-4-carbonyl)-benzenesulfonamide

MS (m/z): 384 (M−1). Analytics calculated for C₂₀H₁₆ClNO₃S: C, 62.25; H,4.18; N, 3.63. Found: C, 61.92; H, 3.91; N, 3.54.

2-Chloro-5-(2′-fluoro-biphenyl-4-carbonyl)-benzenesulfonamide

MS (m/z): 388 (M−1). Analytics calculated for C₁₉H₁₃ClNO₃S: C, 58.54; H,3.36; N, 3.59. Found: C, 58.31; H, 3.50; N, 3.52.

2-Chloro-5-(4′-fluoro-biphenyl-4-carbonyl)-benzenesulfonamide

MS (m/z): 388 (M−1). Analytics calculated for C₁₉H₁₃ClNO₃S: C, 58.54; H,3.36; N, 3.59. Found: C, 57.7; H, 3.23; N, 3.46.

2-Chloro-5-(4′-chloro-biphenyl-4-carbonyl)-benzenesulfonamide

MS (m/z): 405 (M−1). Analytics calculated for C₁₉H₁₃Cl₂NO₃S: C, 56.17;H, 3.22; N, 3.45. Found: C, 55.99; H, 2.92; N, 3.41.

5-(3′-Bromo-biphenyl-4-carbonyl)-2-chloro-benzenesulfonamide

MS (m/z): 448 (M−1). Analytics calculated for C₁₉H₁₃BrClNO₃S: C, 50.63;H, 2.91; N, 3.11. Found: C, 50.58; H, 2.89; N, 2.86.

5-(4-Azepan-1-yl-benzoyl)-2-chloro-benzenesulfonamide

¹H NMR (400 MHz, CDCl₃): δ 1.57 (br, 4H), 1.80 (br, 4H), 3.55 (t, 4H,J=4 Hz), 5.18 (s, 2H), 6.90 (d, 2H, J=8 Hz), 7.66 (d, 1H, J=8 Hz), 7.70(d, 2H, J=8 Hz), 7.88 (d, 1H, J=8 Hz), 8.43 (s, 1H). MS (m/z): 393(M+1). Analytics calculated for C₁₉H₂₁ClN₂O₃S: C, 58.08; H, 5.39; N,7.13. Found: C, 58.10; H, 5.21; N, 6.89.

2-Chloro-5-(naphthalene-2-carbonyl)-benzenesulfonamide

MS (m/z): (M−1) 344.

2-Chloro-5-(2,3-dihydro-1H-indole-5-carbonyl)-benzenesulfonamide

MS (m/z): 335 (M−1). Analytics calculated for C₁₅H₁₃ClN₂O₃S: C, 53.49;H, 3.89; N, 8.32. Found: C, 53.50; H, 4.08; N, 7.34. M.P. 55-56

2-Chloro-5-(1H-indole-3-carbonyl)-benzenesulfonamide

MS (m/z): 333 (M−1). Analytics calculated for C₁₅H₁₁ClN₂O₃S: C, 53.82;H, 3.31; N, 8.37. Found: C, 53.84; H, 3.22; N, 8.31.

Example 51

The following analogs were prepared by method B unless otherwise noted.

2-Chloro-5-(3-methyl-benzoyl)-benzenesulfonamide

MS (m/z): 308 (M−1). Analytics calculated for C₁₄H₁₂ClNO₃S: C, 54.28; H,3.9; N, 4.52. Found: C, 54.31; H, 3.67; N, 4.41.

2-Chloro-5-(4-trimethylsilanylethynyl-benzoyl)-benzenesulfonamide

MS (m/z): 390 (M−1). Analytics calculated for C₁₈H₁₈ClNO₃SSi: C, 55.16;H, 4.63; N, 3.57. Found: C, 55.11; H, 4.43; N, 3.44. M.P. 206-208° C.

2-Chloro-5-(4-pyrrol-1-yl-benzoyl)benzenesulfonamide

¹H NMR (400 MHz, CDCl₃): δ 5.18 (s, 2H), 6.40 (t, 2H), 7.15 (t, 2H),7.50 (d, 2H, J=8 Hz), 7.7 (d, 1H, J=8 Hz), 7.87 (d, 2H, J=8 Hz), 7.98(dd, 1H), 8.50 (d, 1H, J=2 Hz). MS (m/z): 359 (M−1). Analyticscalculated for C₁₇H₁₃ClN₂O₃S: C, 56.59; H, 3.63; N, 7.76. Found: C,56.64; H, 3.85; N, 7.36.

2-Chloro-5-(1H-indole-5-carbonyl)-benzenesulfonamide

MS (m/z): 335 (M+1). Analytics calculated for C₁₅H₁₁ClN₂O₃S: C, 53.82;H, 3.31; N, 8.37. Found: C, 52.39; H, 3.04; N, 7.64. M.P. 65-66° C.

Example 52

The following analogs were prepared by Method C unless otherwise noted.

5-(4-Butyl-benzoyl)-2-chloro-benzenesulfonamide

MS (m/z): 350 (M−1). Analytics calculated for C₁₇H₁₈ClNO₃S: C, 58.03; H,5.16; N, 3.98. Found: C, 58.06; H, 4.86; N, 3.73.

2-Chloro-5-(4-diethylamino-benzoyl)-benzenesulfonamide

¹H NMR (400 MHz, CDCl₃): δ 1.25 (t, 6H, J=2 Hz), 3.45 (q, 4H, J=2 Hz,J=1 Hz), 5.17 (s, 2H), 6.65 (d, 2H, J=8 Hz), 7.64 (d, 1H, J=8 Hz), 7.72(d, 2H, J=8 Hz), 7.86 (d, 1H, J=8 Hz), 8.41 (s, 1H). MS (m/z): 367(M+1).

2-Chloro-5-(4-diallylamino-benzoyl)-benzenesulfonamide

¹H NMR (400 MHz, CDCl₃): δ 4.02 (br, 4H), 5.20 (m, 6H), 5.85 (m, 2H),6.7 (d, 2H, J=9 Hz), 7.6-7.7 (m, 3H), 7.85 (dd, 1H, J=2 Hz), 8.4 (d, 1H,J=2 Hz). MS (m/z): 391 (M+1)

5-[4-(4-Benzyl-piperidin-1-yl)-benzoyl]-2-chloro-benzenesulfonamide

HPLC Reverse Phase (Nucleosil 100-5 C18, gradient 10->100% CH₃CN in 5min) room temperature=5.55 minutes. MS (m/z): 470 (M+1).

2-Chloro-5-(4-morpholin-4-yl-benzoyl)-benzenesulfonamide

¹H NMR (400 MHz, CDCl₃): δ 3.36 (t, 4H, J=4 Hz), 3.87 (t, 4H, J=4 Hz),5.18 (s, 2H), 6.90 (d, 2H, J=8 Hz), 7.66 (d, 1H, J=8 Hz), 7.75 (d, 2H,J=8 Hz), 7.90 (d, 1H, J=8 Hz), 8.43 (s, 1H). MS (m/z): 381 (M+1).

2-Chloro-5-[4-(2-oxo-azetidin-1-yl)-benzoyl]benzenesulfonamide

HPLC Reverse Phase (Nucleosil 100-5 C18, gradient 10->100% CH₃CN in 5min) room temperature=5.17 minutes. MS (m/z): 365 (M+1).

Preparation of 4-benzyl-1-(4-bromo-phenyl)-piperidine

A mixture of 1-bromo-4-iodo benzene (0.500 g), 4-benzylpiperidine (0.25mL), sodium-tert-butylate (0.238 g),tris(dibenzylideneacetone)dipalladium (0.016 g) and2,2′-bis/diphenylphosphino)-1,1′-binaphtyl racemate (0.018 g) isdissolved in tetrahydrofuran and stirred at room temperature overnight.The reaction mixture is concentrated and the resulting residue is loadedon Celite and purified by silica gel chromatography (4:1 hexanes/ethylacetate) to give 4-benzyl-1-(4-bromo-phenyl)-piperidine as a lightyellow syrup. MS (m/z): 331 (M+1).

5-(3H-Benzoimidazole-5-carbonyl)-2-chloro-benzenesulfonamide

The title compound is prepared by analogous methods starting from6-bromo-1H-benzoimidazole. MS (m/z): (M−1) 334; Rf 0.17 (9:1 methylenechloride/methanol).

2-Chloro-5-(1-methyl-1H-indole-5-carbonyl)-benzenesulfonamide

MS (m/z): 347 (M−1). Analytics calculated for C₁₆H₁₃ClN₂O₃S: C, 55.09;H, 3.76; N, 10.16. Found: C, 54.85; H, 3.58; N, 7.65.

2-Chloro-5-[1-(3-methyl-butyl)-1H-indole-5-carbonyl]-benzenesulfonamide

MS (m/z): 403 (M−1). Analytics calculated for C₂₀H₂₁ClN₂O₃S: C, 59.33;H, 5.23; N, 8.76. Found: C, 59.04; H, 5.10; N, 6.91.

Typical Procedure for the Formation of4-(4-chloro-3-sulfamoyl-benzoyl)-N-alkyl-benzamides4-(4-Chloro-3-sulfamoyl-benzoyl)-benzoic acid

A mixture of 500 mg of 2-chloro-5-(4-methyl-benzoyl)-benzenesulfonamide(1.61 mmol, 1 equivalent) in pyridine/water (80/20 mL) is refluxed as 5g of potassium permanganate is added in portions. After the additionsare completed, the reaction is refluxed for 3 h. The reaction is cooledto room temperature, filtered and the filtrate is concentrated in vacuo.The residue is acidified with 1 N HCl, extracted with ethyl acetate andthe combined organic extracts are washed with a saturated sodiumchloride solution, dried over sodium sulfate, and concentrated in vacuoto give 450 mg of the title compound as white solid. MS (m/z): 338(M−1).

Example 53 4-(4-Chloro-3-sulfamoyl-benzoyl)-N-propyl-benzamide

A suspension of 1.2 g of 4-(4-chloro-3-sulfamoyl-benzoyl)-benzoic acid(3.54 mmol, 1 equivalent) in 20 mL of dichloromethane is stirred at roomtemperature as 898 mg of oxalyl chloride (7.08 mmol, 2 equivalents) isadded drop-wise followed by the addition of 2 drops ofN,N,-dimethylformamide. The reaction mixture is stirred at roomtemperature for 2 h and then concentrated in vacuo. The resulting acidchloride is used directly in the next step reaction without furtherpurification.

To a stirred solution of 200 mg of acid chloride (0.56 mmol, 1equivalent) in 10 mL of dichloromethane is added 132 mg of propylamine.The reaction is stirred at room temperature for 18 h. The reaction isacidified with 1 N HCl and extracted with dichloromethane. The combinedorganic extracts are dried over sodium sulfate and concentrated invacuo. After purification by flash chromatography, 120 mg of product isobtained as white crystals (yield 56%). ¹H NMR (400 MHz, CDCl₃): δ 1.0(t, 3H, J=7 Hz), 1.7 (q, 2H, J=7 Hz), 3.4 (t, 2H, J=2 Hz), 7.75-8.43 (m,7H). MS (m/z): 387 (M+1). Analytics calculated for C₁₇H₁₇ClN₂O₄S: C,53.61; H, 4.50; N, 7.36. Found: C, 53.28; H, 4.42; N, 7.34.

The following compounds were prepared in an analogous manner.

4-(4-Chloro-3-sulfamoyl-benzoyl)-N-phenyl-benzamide

¹H NMR (400 MHz, DMSO): δ 7.10 (t, 1H, J=8 Hz), 7.35 (t, 2H, J=8 Hz),7.75-7.98 (m, 6H), 8.08 (d, 2H, J=8 Hz), 8.31 (d, 1H, J=2 Hz). MS (m/z):415 (M+1). Analytics calculated for C₂₁H₁₇ClN₂O₄S: C, 57.90; H, 3.64; N,6.75. Found: C, 57.89; H, 3.42; N, 6.63.

N-Benzyl-4-(4-chloro-3-sulfamoyl-benzoyl)-benzamide

¹H NMR (400 MHz, CDCl₃): δ 4.61 (br, 2H), 7.2-7.4 (m, 5H), 7.75-8.05 (m,4H), 8.42 (m, 1H). MS (m/z): 427 (M−1). Analytics calculated forC₂₁H₁₇ClN₂O₄S: C, 58.81; H, 4.00; N, 6.53. Found: C, 58.53; H, 4.02; N,6.43.

4-(4-Chloro-3-sulfamoyl-benzoyl)-N-(4-phenyl-butyl)-benzamide

¹H NMR (400 MHz, CDCl₃): δ 1.70 (m, 4H), 2.75 (t, 2H, J=6.5 Hz), 3.55(t, 2H), 5.27 (s, 2H), 6.22 (s, 1H), 7.15 (m 4H), 7.70-7.89 (m, 7H). MS(m/z): 471 (M+1). Analytics calculated for C₂₄H₂₃ClN₂O₄S: C, 61.21; H,4.92; N, 5.95. Found: C, 61.53; H, 5.28; N, 5.91.

N-tert-Butyl-4-(4-chloro-3-sulfamoyl-benzoyl)-benzamide

¹H NMR (400 MHz, MeOD): δ 1.48 (s, 9H), 7.75-7.98 (m, 6H), 8.42 (d, 1H,J=2 Hz). MS (m/z): 395 (M+1).

2-Chloro-5-[4-(pyrrolidine-1-carbonyl)-benzoyl]-benzenesulfonamide

¹H NMR (400 MHz, CDCl₃): δ 1.88-2.05 (m, 4H), 3.40 (t, 2H, J=6.5 Hz),3.55 (br, 1H), 3.65 (t, 2H, J=6.5 Hz), 5.31 (s, 2H), 7.58-7.99 (m, 6H),8.48 (d, 1H, J=2 Hz). MS (m/z): 393 (M+1). Analytics calculated forC₁₈H₁₇ClN₂O₄S: C, 55.03; H, 4.36; N, 7.13. Found: C, 55.24; H, 4.29; N,7.45.

4-(4-Chloro-3-sulfamoyl-benzoyl)-N-phenethyl-benzamide

¹H NMR (400 MHz, CDCl₃): δ 3.00 (t, 2H), 3.83 (t, 2H), 5.22 (s, 2H),6.27 (br, 1H), 7.2-7.35 (m, 5H), 7.72-8.0 (m, 6H), 8.45 (s, 1H). MS(m/z): 443 (M+1). Analytics calculated for C₂₂H₁₉ClN₂O₄S: C, 59.66; H,4.32; N, 6.32. Found: C, 60.00; H, 4.71; N, 6.13.

Typical Procedure for Suzuki Couplings of5-(4-bromo-benzoyl)-2-chloro-benzenesulfonamide2-Chloro-5-(3′-nitro-biphenyl-4-carbonyl)benzenesulfonamide

A mixture of 220 mg of 5-(4-bromo-benzoyl)-2-chloro-benzenesulfonamide(0.587 mmol, 1 equivalent), 196 mg of 3-nitrobenzene boronic acid (1.174mmol, 2 equivalent), 556 mg of Ba(OH)₂ (1.761 mmol, 3 equivalent), and14 mg of Pd(PPh₃)₄ in degassed dioxane/water (30 mL/10 mL) is refluxedfor 18 h. The reaction is quenched with 1 N HCl and extracted with ethylacetate. The combined organic extracts are dried over sodium sulfate,and concentrated in vacuo. After purification by flash chromatography,50 mg of the title compound is obtained as white solid. ¹H NMR (400 MHz,CDCl₃): δ 5.2 (br, 2H), 6.18 (br, 1H), 7.02 (d, 2H, J=8 Hz), 7.12-7.45(m, 5H), 7.6-7.8 (m, 3H), 7.90 (dd, 1H), 8.41 (s, 1H). MS (m/z): 387(M+1).

The following compounds were made by analogous procedures

2-Chloro-5-(4-naphthalen-2-yl-benzoyl)-benzenesulfonamide

MS (m/z): 420 (M−1). Analytics calculated for C₂₃H₁₆ClNO₃S: C, 65.48; H,3.82; N, 3.32. Found: C, 65.19; H, 3.97; N, 3.19. M.P. 193-195° C.

2-Chloro-5-(4-thiophen-2-yl-benzoyl)-benzenesulfonamide

MS (m/z): 376 (M−1). M.P. 146-148° C.

2-Chloro-5-(4-thiophen-3-yl-benzoyl)-benzenesulfonamide

MS (m/z): 376 (M−1)⁻. Analytics calculated for C₁₇H₁₂ClNO₃S₂: C, 54.04;H, 3.2; N, 3.71. Found: C, 54.12; H, 3.09; N, 3.52.

2-Chloro-5-(4-pyridin-3-yl-benzoyl)-benzenesulfonamide

MS (m/z): 371 (M−1). Analytics calculated for C₁₈H₁₃ClN₂O₃S: C, 57.99;H, 3.51; N, 7.51. Found: C, 58.41; H, 3.49; N, 7.07. M.P. 190-192° C.

2-Chloro-5-(4-pyridin-4-yl-benzoyl)-benzenesulfonamide

MS (m/z): 371 (M−1).

2-Chloro-5-[4-(2-chloro-pyridin-4-yl)-benzoyl]-benzenesulfonamide

MS (m/z): 406 (M−1). Analytics calculated for C₁₈H₁₂Cl₂N₂O₃S: C, 53.08;H, 2.97; N, 6.88. Found: C, 52.72; H, 3.10; N, 6.97. M.P. 218-220° C.

2-Chloro-5-(3′-methyl-biphenyl-4-carbonyl)-benzenesulfonamide

MS (m/z): 384 (M−1). Analytics calculated for C₂₀H₁₆ClNO₃S: C, 62.25; H,4.18; N, 3.63. Found: C, 62.28; H, 3.98; N, 3.45. M.P. 176-178° C.

2-Chloro-5-(4′-trifluoromethyl-biphenyl-4-carbonyl)-benzenesulfonamide

MS (m/z): 438 (M−1). Analytics calculated for C₂₀H₁₃ClF₃NO₃S: C, 54.62;H, 2.98; N, 3.18. Found: C, 54.63; H, 2.56; N, 3.00. M.P. 117-119° C.

2-Chloro-5-(4′-ethyl-biphenyl-4-carbonyl)-benzenesulfonamide

MS (m/z): 398 (M−1). Analytics calculated for C₂₁H₁₈ClNO₃S: C, 63.07; H,4.54; N, 3.5. Found: C, 63.14; H, 4.35; N, 3.42.

5-(3′-Amino-biphenyl-4-carbonyl)-2-chloro-benzenesulfonamide

MS (m/z): 385 (M−1). Analytics calculated for C₁₉H₁₅ClN₂O₃S: C, 58.99;H, 3.91; N, 7.24. Found: C, 59.30; H, 3.78; N, 7.33. M.P. 228-230° C.

N-[4′-(4-Chloro-3-sulfamoyl-benzoyl)-biphenyl-3-yl]acetamide

¹H NMR (400 MHz, CDCl₃): δ 2.23 (s, 3H), 5.2 (s, 2H), 7.38-8.0 (m, 10H),8.5 (s, 1H). MS (m/z): 429 (M+1). Analytics calculated forC₂₁H₁₇ClN2O₄S: C, 58.81; H, 4.00; N, 6.53. Found: C, 58.99; H, 3.90; N,6.19.

2-Chloro-5-(3′-hydroxymethyl-biphenyl-4-carbonyl)-benzenesulfonic acid

¹H NMR (400 MHz, CDCl₃): δ 4.81 (s, 2H), 5.17 (s, 2H), 7.40-7.90 (m,9H), 8.01 (d, 1H, J=8 Hz), 8.53 (s, 1H). MS (m/z): 400 (M−1).

2-Chloro-5-(4′-formyl-biphenyl-4-carbonyl)-benzenesulfonamide

MS (m/z): 398 (M−1).

4′-(4-Chloro-3-sulfamoyl-benzoyl)-biphenyl-4-carboxylic acid

MS (m/z): 414 (M−1). Analytics calculated for C₂₀H₁₄ClNO₅S: C, 57.76; H,3.39; N, 3.37. Found: C, 57.45; H, 3.05; N, 3.25.

4′-(4-Chloro-3-sulfamoyl-benzoyl)-biphenyl-4-carboxylic acid methylester

MS (m/z): 428 (M−1). Analytics calculated for C₂₁H₁₆ClNO₅S₂: C, 58.67;H, 3.75; N, 3.26. Found: C, 58.29; H, 3.72; N, 3.20.

5-(3′-Benzyloxy-biphenyl-4-carbonyl)-2-chloro-benzenesulfonamide

MS (m/z): 476 (M−1).

2-Chloro-5-(2′-methyl-biphenyl-4-carbonyl)-benzenesulfonamide

MS (m/z): 384 (M−1). Analytics calculated for C₂₀H₁₆ClNO₃S: C, 62.25; H,4.18; N, 3.63. Found: C, 62.64; H, 4.18; N, 3.63. M.P. 98-100° C.

2-Chloro-5-(3′-trifluoromethyl-biphenyl-4-carbonyl)-benzenesulfonamide

MS (m/z): 438 (M−1). Analytics calculated for C₂₀H₁₃ClF₃NO₃S: C, 54.62;H, 2.98; N, 3.18. Found: C, 55.27; H, 2.97; N, 2.84. M.P. 75-77° C.

The following two examples were also synthesized via palladium mediatedcross coupling.

2-Chloro-5-(4-ethynyl-benzoyl)-benzenesulfonamide

MS (m/z): 318 (M−1). Analytics calculated for C₁₅H₁₀ClNO₃S: C, 56.34; H,3.15; N, 4.38. Found: C, 56.19; H, 2.88; N, 4.24. M.P. 147-149° C.

2-Chloro-5-(4-phenylamino-benzoyl)-benzenesulfonamide

¹H NMR (400 MHz, CDCl₃): δ 5.2 (br, 2H), 6.18 (br, 1H), 7.02 (d, 2H, J=8Hz), 7.12-7.45 (m, 5H), 7.6-7.8 (m, 3H), 7.90 (dd, 1H), 8.41 (s, 1H). MS(m/z): 387 (M+1).

Example 54 General Synthesis of Indazole Analogs

A Typical Procedure for Acylation-Fries Rearrangement

To a solution of 3-bromophenol (1.0 equivalent) in methylene chloride (5vol) is added aluminum chloride (1.5 equivalent) followed by acidchloride (1.0 equivalent). The mixture is heated to reflux for 2-3 h,cooled to room temperature, and the mixture is poured slowly into abeaker containing ice and 2 N HCl and extracted with methylene chloride.The combined organic extracts are dried over sodium sulfate, filtered,and concentrated to a crude solid, which is purified by flashchromatography.

General Procedure for Mesylate Formation

To a solution of phenol (1.0 equivalent) in dichloromethane (5 vol) isadded triethylamine (2.0 equivalent). The resulting solution is cooledto 0° C. and methylsulfonyl chloride (1.1 equivalent) is addeddrop-wise. The reaction is stirred at room temperature for (30 minutesto 18 h), poured into 1 N HCl and extracted with dichloromethane. Thecombined organic extracts are dried over sodium sulfate, filtered, andconcentrated to give the crude product, which is purified by flashchromatography.

General Procedure for Indazole Formation

The mesylate (1.0 equivalent) is combined with the HCl salt of thebenzyl hydrazine (1.5 equivalent) and sodium acetate (3.0 equivalent) inxylenes (6 vol). The mixture is heated to reflux in a Dean-Starkapparatus until completion. The reaction is cooled to room temperature,poured into 1 N HCl and extracted with toluene. The combined organicextracts are dried over sodium sulfate and concentrated to afford thecrude indazole which is purified by flash chromatography.

General Procedure for N-Debenzylation

Benzyl-indazole is dissolved in dimethylsulfoxide and potassiumtert-butoxide (1 M solution in tetrahydrofuran) is added at roomtemperature. Oxygen is then bubbled into the solution for 5 minutes. Thereaction is allowed to stir at room temperature for 18 h. The reactionis quenched with aqueous saturated ammonium chloride then extractedthree times with ethyl acetate. The combined organic extracts are driedover sodium sulfate, and concentrated. Purification by flashchromatography provides the deprotected indazole.

Example 552-Chloro-5-(3-ethyl-1H-indazole-6-carbonyl)-benzenesulfonamide

¹H NMR (400 MHz, CDCl₃): δ 1.45 (t, 3H, J=8 Hz), 3.06 (q, 2H, J=8 Hz),5.24 (2H), 7.57 (d, 1H, J=0.16 Hz), 7.71 (d, 1H, J=0.16 Hz), 7.86-7.82(m, 4H), 8.52 (s, 1H). MS (m/z): 364 (M+1).

Example 562-Chloro-5-(3-methyl-1H-indazole-6-carbonyl)-benzenesulfonamide

¹H NMR (400 MHz, MeOD). δ 2.61 (s, 3H), 7.54 (m, 1H), 7.78 (1H), 7.88(1H), 7.98 (1H), 8.48 (1s, 1H). MS (m/z): 350 (M+1).

Example 572-Chloro-5-(3-isopropyl-1H-indazole-6-carbonyl)-benzenesulfonamide

¹H NMR (400 MHz, CDCl₃): δ 1.48 (d, 6H, J=8 Hz), 3.47 (m, 1H), 5.24 (m,2H), 7.55 (d, 1H, J=4 Hz), 7.71 (d, 1H, J=4 Hz), 7.86-7.89 (m, 2H), 8.01(d, 1H, J=4 Hz), 8.52 (s, 1H). MS (m/z): 378 (M+1).

Example 585-(1-Benzyl-3-ethyl-1H-indazole-6-carbonyl)-2-chloro-benzenesulfonamide

¹H NMR (400 MHz, CDCl₃): δ 1.35 (t, 3H, J=7.7 Hz), 3.06 (q, 2H, J=7.7Hz), 5.15 (m, 2H), 5.58 (2H), 7.19 (d, 2H, J=8 Hz), 7.28-7.86 (m, 8H),8.48 (d, 1H, J=4 Hz). MS (m/z): 454.1 (M+1).

Example 592-Chloro-5-[3-(2-cyclopentyl-ethyl)-1H-indazole-6-carbonyl]-benzenesulfonamide

¹H NMR (400 MHz, CDCl₃): δ 1.25 (m, 2H), 1.5-1.7 (m, 6H), 1.85 (m, 5H),3.03 (t, 2H), 5.34 (s, 2H), 7.56 (d, 1H, J=4 Hz), 7.70 (d, 1H), 7.83 (m,2H), 8.0 (1H), 8.5 (s, 1H). MS (m/z): 432 (M+1).

Table 1 below shows the inhibitory activity (IC₅₀ values) ofrepresentative compounds to MMP02 and MMP13.

TABLE 1 MMP02 MMP13 MW MW Example # IUPAC Name IC₅₀ (μM) IC₅₀ (μM)(Calc'd) (Found) 1 3-(4-Methoxy- 1.92 2.49 291.33 290 (M − 1) benzoyl)-benzenesulfonamide 2 2-Fluoro-5-(4- 2.41 1.59 309.32 308 (M − 1)methoxy-benzoyl)- benzenesulfonamide 3 2-Chloro-5-(4- 5.18 2.02 325.77326 (M + 1) methoxy-benzoyl)- benzenesulfonamide 4 2,3-Difluoro-5-(4-4.68 5.73 325.77 326 (M − 1) methoxy-benzoyl)- benzenesulfonamide 55-(4-Methoxy- 1.06 1.39 336.33 335 (M − 1) benzoyl)-2-nitro-benzenesulfonamide 6 5-(4-Methoxy- 2.78 4.51 360.22 306 (M + 1)benzoyl)-2-methyl- benzenesulfonamide 7 5-(4-Methoxy- 2.36 3.72 360.22336 (M − 1) benzoyl)-2- methylsulfanyl- benzenesulfonamide 82-Methanesulfinyl-5- 4.48 10.74 336.33 352 (M − 1) (4-methoxy-benzoyl)-benzenesulfonamide 9 2-Methanesulfonyl-5- 2.93 11.35 305.36 368 (M − 1)(4-methoxy-benzoyl)- benzenesulfonamide 10 3-[3-(2-Methyl-pyridin- 3.40.03 391.45 390 (M − 1) 4-yl)-1H-indole-6- carbonyl]- benzenesulfonamide11 3-{3-[2-(3-Methoxy- 3.95 0.075 449.53 450 (M + 1)propyl)-pyridin-4-yl]- 1H-indole-6-carbonyl}- benzenesulfonamide 122-Chloro-5-(4- 9.13 3.04 429.93 430.0 (M + 1)   methoxy-benzoyl)-N-phenethyl- benzenesulfonamide 13 2-Chloro-N-[2-(4- 8.8 6.9 447.92 448.0(M + 1)   fluoro-phenyl)-ethyl]-5- (4-methoxy-benzoyl)-benzenesulfonamide 14 3-{3-[2-(3-Morpholin-4- 0.8 0.01 504.61 505(M + 1) yl-propyl)-pyridin-4-yl]- 1H-indole-6-carbonyl}-benzenesulfonamide 15 2-Chloro-5-(4-hydroxy- 5.16 10 311.75 310 (M − 1)benzoyl)- benzenesulfonamide 16 2-Chloro-5-[4-(2- 5.94 4.9 341.77 342(M + 1) hydroxy-ethoxy)- benzoyl]- benzenesulfonamide 17 2-Chloro-5-(4-2.30 3.71 355.8 354 (M − 1) isobutoxy-benzoyl)- benzenesulfonamide 182-Chloro-5-[4-(3- 0.7 0.6 367.85 368 (M + 1) methyl-butoxy)- benzoyl]-benzenesulfonamide 19 2-Chloro-5-[4-(3- 1.58 1.22 367.85 366 (M − 1)phenyl-propoxy)- benzoyl]- benzenesulfonamide 20 2-Chloro-5-(4- 11 13.6351.81 350 (M − 1) pentyloxy-benzoyl)- benzenesulfonamide 212-Chloro-5-(4- 4.73 0.86 381.88 380 (M − 1) hexyloxy-benzoyl)-benzenesulfonamide 22 5-(4-Bromo-benzoyl)- 14 2.05 429.93 430 (M + 1)2-chloro- benzenesulfonamide 23 5-(4-Bromo-benzoyl)- 4.15 0.95 381.88382 (M + 1) 2-chloro- benzenesulfonamide 24 2-Chloro-5-(3-methyl- 9.162.1 395.91 396 (M + 1) benzoyl)- benzenesulfonamide 25 2-Chloro-5-(4-2.17 5.3 374.64 448 (M − 1) trifluoromethoxy- benzoyl)-benzenesulfonamide 26 5-(4-tert-Butyl- 17.2 10.53 309.77 308 (M − 1)benzoyl)-2-chloro- benzenesulfonamide 27 2-Chloro-5-(4- 7.46 9.64 379.74378 (M − 1) cyclopropyl-benzoyl)- benzenesulfonamide 28 2-Chloro-5-(4-4.26 4.49 381.85 350 (M − 1) cyclopentyl-benzoyl)- benzenesulfonamide 292-Chloro-5-(4- 13.26 11.32 381.85 352 (M + 1) cyclohexyl-benzoyl)-benzenesulfonamide 30 2-Chloro-5-(4- 1.23 1.69 335.81 334 (M − 1)trimethylsilanylethynyl- benzoyl)- benzenesulfonamide 312-Chloro-5-(4-ethynyl- 10.44 12.41 363.87 370 (M − 1) benzoyl)-benzenesulfonamide 32 2-Chloro-5-(4- 8.3 10.02 377.89 376 (M − 1)phenylethynyl- benzoyl)- benzenesulfonamide 33 4-(4-Chloro-3- >30 2.59391.95 390 (M − 1) sulfamoyl-benzoyl)-N- propyl-benzamide 344-(4-Chloro-3- 2.51 4.71 319.77 318 (M − 1) sulfamoyl-benzoyl)-N-phenyl-benzamide 35 N-Benzyl-4-(4-chloro- 6.89 0.84 395.87 394 (M − 1)3-sulfamoyl-benzoyl)- benzamide 36 4-(4-Chloro-3- 14.9 8.54 380.85 387(M + 1) sulfamoyl-benzoyl)-N- (2-pyridin-2-yl-ethyl)- benzamide 374-(4-Chloro-3- 22.8 8.9 414.87 415 (M + 1) sulfamoyl-benzoyl)-N-(4-phenyl-butyl)- benzamide 38 2-Chloro-5-(4- 14.54 8.58 428.9 427 (M− 1) naphthalen-2-yl- benzoyl)- benzenesulfonamide 39 2-Chloro-5-(4-13.3 9.06 443.91 442.0 (M − 1)   thiophen-2-yl-benzoyl)-benzenesulfonamide 40 2-Chloro-5-(4- >30 7.06 470.98 471 (M + 1)thiophen-3-yl-benzoyl)- benzenesulfonamide 41 2-Chloro-5-(4-pyridin- >97.52 421.91 420 (M − 1) 3-yl-benzoyl)- benzenesulfonamide 422-Chloro-5-(4-pyridin- 0.51 1.5 377.87 376 (M − 1) 4-yl-benzoyl)-benzenesulfonamide 43 2-Chloro-5-[4-(2- 0.30 0.38 377.87 376 (M − 1)chloro-pyridin-4-yl)- benzoyl]- benzenesulfonamide 442-Chloro-5-(4-cyano- 0.62 0.56 372.83 371 (M − 1) benzoyl)-benzenesulfonamide 45 5-(2-Bromo-4-methyl- 0.053 0.08 372.83 371 (M − 1)benzoyl)-2-chloro- benzenesulfonamide 46 5-(4-Bromo-2-methyl- 0.15 0.21407.28 406 (M − 1) benzoyl)-2-chloro- benzenesulfonamide 472-Chloro-5-(3-fluoro-4- 17.3 11.1 320.76 319 (M − 1) hydroxy-benzoyl)-benzenesulfonamide 48 2-Chloro-5-(2,4- >30 25.3 388.67 386 (M − 1)dimethoxy-benzoyl)- benzenesulfonamide 49 5-Benzoyl-2-chloro- >30 24.8388.67 386 (M − 1) benzenesulfonamide 50 2-Chloro-5-(2-fluoro-4- 24.321.3 343.76 342 (M − 1) hydroxy-benzoyl)- benzenesulfonamide 512-Chloro-5-(4-fluoro- 14.6 18.7 329.74 330 (M + 1) benzoyl)-benzenesulfonamide 52 N-tert-Butyl-4-(4- 29.1 21.3 355.8 356 (M + 1)chloro-3-sulfamoyl- benzoyl)-benzamide 53 2-Chloro-5-[4- >30 >30 295.75294 (M − 1) (pyrrolidine-1- carbonyl)-benzoyl]- benzenesulfonamide 544-(4-Chloro-3- 23.4 27.1 329.74 330 (M + 1) sulfamoyl-benzoyl)-N-phenethyl-benzamide 55 2-Chloro-5-(4-hydroxy- 25.5 27.5 313.74 312 (M− 1) benzoyl)- benzenesulfonamide 56 2-Chloro-5-(3-hydroxy- >30 26.7394.88 395 (M + 1) 4-methoxy-benzoyl)- benzenesulfonamide 572-Chloro-5-[4-(2- >30 21.2 392.86 393 (M + 1) hydroxy-ethoxy)- benzoyl]-benzenesulfonamide 58 2-Chloro-5-(4- >30 24.2 442.92 443 (M + 1)isobutoxy-benzoyl)- benzenesulfonamide 59 5-(Biphenyl-4- 1.16 2.63371.85 370 (M − 1) carbonyl)-2-chloro- benzenesulfonamide 602-Chloro-5-(3′-methyl- 6.31 5.44 385.87 384 (M − 1)biphenyl-4-carbonyl)- benzenesulfonamide 61 2-Chloro-5-(4′-methyl- 1.11.02 385.87 384 (M − 1) biphenyl-4-carbonyl)- benzenesulfonamide 622-Chloro-5-(4′- 2.21 0.83 439.84 438 (M − 1) trifluoromethyl-biphenyl-4-carbonyl)- benzenesulfonamide 63 2-Chloro-5-(4′-ethyl- 2.050.38 399.9 398 (M − 1) biphenyl-4-carbonyl)- benzenesulfonamide 642-Chloro-5-(2′-fluoro- 4.05 7.55 389.84 388 (M − 1)biphenyl-4-carbonyl)- benzenesulfonamide 65 2-Chloro-5-(4′-fluoro- 1.181.61 389.84 388 (M − 1) biphenyl-4-carbonyl)- benzenesulfonamide 662-Chloro-5-(4′-chloro- 0.72 0.63 406.29 405 (M − 1)biphenyl-4-carbonyl)- benzenesulfonamide 67 5-(3′-Bromo-biphenyl- 10.25.29 450.74 488 (M − 1) 4-carbonyl)-2-chloro- benzenesulfonamide 682-Chloro-5-(3′-nitro- 3.44 3.15 416.84 387 (M + 1) biphenyl-4-carbonyl)-benzenesulfonamide 69 5-(3′-Amino-biphenyl- 1.37 2.41 386.86 385 (M − 1)4-carbonyl)-2-chloro- benzenesulfonamide 70 N-[4′-(4-Chloro-3- 11.434.01 428.9 429 (M + 1) sulfamoyl-benzoyl)- biphenyl-3-yl]- acetamide 712-Chloro-5-(3′- 1.09 1.4 402.86 400 (M − 1) hydroxymethyl-biphenyl-4-carbonyl)- benzenesulfonic acid 72 2-Chloro-5-(4′-formyl-0.18 0.13 399.86 398 (M − 1) biphenyl-4-carbonyl)- benzenesulfonamide 734′-(4-Chloro-3- 0.98 0.61 415.86 414 (M − 1) sulfamoyl-benzoyl)-biphenyl-4-carboxylic acid 74 4′-(4-Chloro-3- 0.93 0.24 429.88 428 (M− 1) sulfamoyl-benzoyl)- biphenyl-4-carboxylic acid methyl ester 752-Chloro-5-(3′- >30 25.9 439.84 476 (M − 1) trifluoromethyl-biphenyl-4-carbonyl)- benzenesulfonamide 76 5-(Biphenyl-4- 21.7 12.0371.85 384 (M − 1) carbonyl)-2-chloro- benzenesulfonamide 772-Chloro-5-(3′-methyl- 29.1 23.1 385.87 438 (M − 1)biphenyl-4-carbonyl)- benzenesulfonamide 78 2-Chloro-5-(4- 0.27 0.35338.82 339 (M + 1) dimethylamino- benzoyl)- benzenesulfonamide 792-Chloro-5-(4- 5.72 10.42 366.87 367 (M + 1) diethylamino-benzoyl)-benzenesulfonamide 80 2-Chloro-5-(4- 0.055 0.113 364.85 365 (M + 1)pyrrolidin-1-yl- benzoyl)- benzenesulfonamide 81 2-Chloro-5-[4-(2,5-1.31 1.01 362.84 361 (M − 1) dihydro-pyrrol-1-yl)- benzoyl]-benzenesulfonamide 82 2-Chloro-5-(4-pyrrol-1- 1.15 0.86 360.82 359 (M− 1) yl-benzoyl)- benzenesulfonamide 83 2-Chloro-5-(4- 0.87 1.77 378.88379 (M + 1) piperidin-1-yl-benzoyl)- benzenesulfonamide 842-Chloro-5-[4-(3- 1.35 7.54 392.91 393 (M + 1) methyl-piperidin-1-yl)-benzoyl]- benzenesulfonamide 85 2-Chloro-5-[4-(4- 2.05 0.57 454.98 453(M − 1) phenyl-piperidin-1-yl)- benzoyl]- benzenesulfonamide 865-[4-(4-Benzyl- >30 7.67 469.01 470 (M + 1) piperidin-1-yl)-benzoyl]-2-chloro- benzenesulfonamide 87 2-Chloro-5-[4-(4- 1.74 1.19393.9 394 (M + 1) methyl-piperazin-1-yl)- benzoyl]- benzenesulfonamide88 2-Chloro-5-(4- 0.96 1.84 380.85 381 (M + 1) morpholin-4-yl- benzoyl)-benzenesulfonamide 89 2-Chloro-5-[4-(2-oxo- 2.06 3.34 364.81 365 (M + 1)azetidin-1-yl)-benzoyl]- benzenesulfonamide 90 5-(4-Azepan-1-yl- 13.810.8 392.91 393 (M + 1) benzoyl)-2-chloro- benzenesulfonamide 912-Chloro-5-(4- >30 22.5 474.92 391 (M + 1) methoxy-benzoyl)-N-[2-(4-nitro-phenyl)- ethyl]- benzenesulfonamide 92 2-Chloro-5-(4- 22.820.7 386.86 387 (M + 1) phenylamino-benzoyl)- benzenesulfonamide 932-Chloro-5- 26.5 13.71 345.81 344 (M − 1) (naphthalene-2- carbonyl)-benzenesulfonamide 94 2-Chloro-5-(indane-5- 23.5 22.6 335.81 336 (M + 1)carbonyl)- benzenesulfonamide 95 2-Chloro-5-(1H- 3.97 6.21 284.72 285(M + 1) pyrrole-3-carbonyl)- benzenesulfonamide 962-Chloro-5-(thiophene- 10 14.7 301.77 300.0 (M − 1)   2-carbonyl)-benzenesulfonamide 97 5-(3H-Benzoimidazole- 1.21 0.63 335.77 334 (M − 1)5-carbonyl)-2-chloro- benzenesulfonamide 98 2-Chloro-5-(2-methyl- 2.258.31 349.8 348 (M − 1) 3H-benzoimidazole-5- carbonyl)-benzenesulfonamide 99 2-Chloro-5-(3-ethyl- 0.27 0.25 363.83 364 (M + 1)1H-indazole-6- carbonyl)- benzenesulfonamide 100 2-Chloro-5-(3-methyl-0.26 0.25 349.8 350 (M + 1) 1H-indazole-6- carbonyl)- benzenesulfonamide101 2-Chloro-5-(3- 6.35 3.65 377.85 378 (M + 1) isopropyl-1H-indazole-6-carbonyl)- benzenesulfonamide 102 5-(9H-Carbazole-2- 1.01 2.71 384.84385 (M + 1) carbonyl)-2-chloro- benzenesulfonamide 103 7-(4-Chloro-3-0.85 0.36 461.93 462 (M + 1) sulfamoyl-benzoyl)- 1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2- carboxylic acid ethyl ester 104 8-(4-Chloro-3-21.45 1.9 461.93 462 (M + 1) sulfamoyl-benzoyl)- 1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2- carboxylic acid ethyl ester 1052-Chloro-5-(1-oxo- 8 9 403.85 402.0 (M − 1)   2,3,4,9-tetrahydro-1H-beta-carboline-7- carbonyl)- benzenesulfonamide 1062-Chloro-5-[2-(2,2- >2.7 0.95 473.98 472.1 (M − 1)  dimethyl-propionyl)- 2,3,4,9-tetrahydro-1H- beta-carboline-6- carbonyl]-benzenesulfonamide 107 2-Chloro-5-(1-methyl- 0.027 0.069 416.89 417(M + 1) 2-oxo-2,3,4,9- tetrahydro-1H- indeno[2,1-b]pyridine-7-carbonyl)- benzenesulfonamide 108 2-Chloro-5-(1-ethyl-2- 2.9 4.11430.91 431 (M + 1) oxo-2,3,4,9-tetrahydro- 1H-indeno[2,1-b]pyridine-7-carbonyl)- benzenesulfonamide 109 2-Chloro-5-[4-(2,5- 21.819.9 406.87 407 (M + 1) dimethyl-pyrrol-1-yl)-3- fluoro-benzoyl]-benzenesulfonamide 110 2-Chloro-5-(2,3- 12.0 16.1 336.8 335 (M − 1)dihydro-1H-indole-5- carbonyl)- benzenesulfonamide 1115-(1-Benzyl-3-ethyl- >30 25.3 453.95 454 (M + 1) 1H-indazole-6-carbonyl)-2-chloro- benzenesulfonamide 112 2-Chloro-5-[3-(2- 2.95 0.129431.94 432 (M + 1) cyclopentyl-ethyl)-1H- indazole-6-carbonyl]-benzenesulfonamide 113 2-Chloro-5-(1H-indole- 8.94 3.08 334.78 333 (M− 1) 3-carbonyl)- benzenesulfonamide 114 2-Chloro-5-(1-methyl- 3.31 3.13348.81 347 (M − 1) 1H-indole-5-carbonyl)- benzenesulfonamide 1152-Chloro-5-(1H-indole- 0.218 0.178 334.78 333 (M − 1) 6-carbonyl)-benzenesulfonamide 116 2-Chloro-5-(1H-indole- 15.4 15.3 334.78 335(M + 1) 5-carbonyl)- benzenesulfonamide 117 2-Chloro-5-[1-(3- 26.7 23.0404.92 403 (M − 1) methyl-butyl)-1H- indole-5-carbonyl]-benzenesulfonamide 118 2-Chloro-5-(3-phenyl- 2.00 1.03 410.88 409 (M− 1) 1H-indole-6-carbonyl)- benzenesulfonamide 119 2-Chloro-5-[3-(4- 246.04 440.91 439 (M − 1) methoxy-phenyl)-1H- indole-6-carbonyl]-benzenesulfonamide 120 2-Chloro-5-[3-(4- 1.9 0.95 428.87 427 (M − 1)fluoro-phenyl)-1H- indole-6-carbonyl]- benzenesulfonamide 1215-[3-(3-Acetyl-phenyl)- 3.9 0.59 452.92 452 (M − 1)1H-indole-6-carbonyl]- 2-chloro- benzenesulfonamide 1225-[3-(4-Acetyl-phenyl)- 12.5 1.45 452.92 451 (M − 1)1H-indole-6-carbonyl]- 2-chloro- benzenesulfonamide 1232-Chloro-5-[3-(3- 5.02 0.39 488.97 487 (M − 1) methanesulfonyl-phenyl)-1H-indole-6- carbonyl]- benzenesulfonamide 124 2-Chloro-5-[3-(4-19.7 0.54 488.97 487 (M − 1) methanesulfonyl- phenyl)-1H-indole-6-carbonyl]- benzenesulfonamide 125 2-Chloro-5-[3-(4- >30 1.01 503 501 (M− 1) ethanesulfonyl- phenyl)-1H-indole-6- carbonyl]- benzenesulfonamide126 5-(3-Biphenyl-4-yl-1H- 22.8 10 486.98 485 (M − 1)indole-6-carbonyl)-2- chloro- benzenesulfonamide 127 2-Chloro-5-(3- 4.61.6 416.91 415 (M − 1) thiophen-3-yl-1H- indole-6-carbonyl)-benzenesulfonamide 128 5-[3-(5-Acetyl- 6.9 0.16 458.95 451 (M − 1)thiophen-2-yl)-1H- indole-6-carbonyl]-2- chloro- benzenesulfonamide 1295-(1H,1′H- 2.95 1.65 449.92 447 (M − 1) [3,5′]Biindolyl-6-carbonyl)-2-chloro- benzenesulfonamide 130 2-Chloro-5-(3-pyridin- 2.620.24 411.87 410 (M − 1) 3-yl-1H-indole-6- carbonyl)- benzenesulfonamide131 2-Chloro-5-(3- 4 0.195 412.86 411 (M − 1) pyrimidin-5-yl-1H-indole-6-carbonyl)- benzenesulfonamide 132 2-Chloro-5-{3-[4- 16 0.73 524522 (M − 1) (morpholine-4- carbonyl)-phenyl]-1H- indole-6-carbonyl}-benzenesulfonamide 133 2-Chloro-5-[3-(3,5- 23 0.30 429.89 428 (M − 1)dimethyl-isoxazol-4- yl)-1H-indole-6- carbonyl]- benzenesulfonamide 1342-Chloro-5-[3-(5- 23 0.10 476.34 474 (M − 1) chloro-2-methoxy-pyridin-4-yl)-1H-indole- 6-carbonyl]- benzenesulfonamide 1352-Chloro-5-(3-pyridin- 1.05 0.09 411.87 410 (M − 1) 4-yl-1H-indole-6-carbonyl)- benzenesulfonamide 136 2-Chloro-5-[3-(2- 18 0.25 446.31 444(M − 1) chloro-pyridin-4-yl)-1H- indole-6-carbonyl]- benzenesulfonamide137 2-Chloro-5-[3-(2- 3.45 0.041 425.9 424 (M − 1) methyl-pyridin-4-yl)-1H-indole-6-carbonyl]- benzenesulfonamide 138 2-Chloro-5-[3-(2-ethyl-3.55 0.06 439.92 438 (M − 1) pyridin-4-yl)-1H-indole- 6-carbonyl]-benzenesulfonamide 139 2-Chloro-5-[3-(2- 4.15 0.068 451.94 450 (M − 1)cyclopropyl-pyridin-4- yl)-1H-indole-6- carbonyl]- benzenesulfonamide140 2-Chloro-5-{3-[2-(3- 0.36 0.007 483.98 482 (M − 1) methoxy-propyl)-pyridin-4-yl]-1H-indole- 6-carbonyl}- benzenesulfonamide 1412-Chloro-5-{3-[2-(3- 1.1 0.02 539.06 539 (M + 1) morpholin-4-yl-propyl)-pyridin-4-yl]-1H-indole- 6-carbonyl}- benzenesulfonamide 1422-Chloro-5-{3-[2-(2- 0.2 0.017 498.99 497 (M − 1) dimethylamino-ethoxy)-pyridin-4-yl]- 1H-indole-6-carbonyl}- benzenesulfonamide 1432-Chloro-5-{3-[2-(2- 2.85 0.15 541.03 539 (M − 1) morpholin-4-yl-ethoxy)-pyridin-4-yl]- 1H-indole-6-carbonyl}- benzenesulfonamide 1442-Fluoro-5-(1H-indole- 0.39 0.3 318.33 317 (M − 1) 6-carbonyl)-benzenesulfonamide 145 5-(1H-Indole-6- 0.20 0.1 314.37 313 (M − 1)carbonyl)-2-methyl- benzenesulfonamide 146 3-(1H-Indole-6- 0.24 0.2300.34 299 (M − 1) carbonyl)- benzenesulfonamide 147 2-Methyl-5-[3-(2-2.4 0.02 405.48 404 (M − 1) methyl-pyridin-4-yl)- 1H-indole-6-carbonyl]-benzenesulfonamide

Other Embodiments

Other embodiments will be evident to those of skill in the art. Itshould be understood that the foregoing detailed description is providedfor clarity only and is merely exemplary. The spirit and scope of thepresent invention are not limited to the above examples, but areencompassed by the following claims.

1. A compound of formula (I)

Wherein R₁ is selected from aryl, heteroaryl, heterocycloalkyl, eachoptionally substituted by one to five substitutents selected from thegroup consisting of 1) alkyl, cycloalkyl, aryl, heteroaryl,heterocycloalkyl, alkoxy, alkoxy-alkyl-, alkoxycarbonyl, R₄—O—, R₅C(O)—,R₆SO₂—, (R₇)NH—C(O)—, or (R₈)(R₉)N—, each of which is further optionallysubstituted by one to two substituents selected from halo, alkoxy,alkyl, hydroxy, dialkylamino, alkylsulfonyl, heterocycloalkyl, andaryloxy; and 2) hydroxy, halo, nitro, amino, carboxy, or HC(O)—; R₂ andR₃ are independently hydrogen, or (C₁-C₇) alkyl; R₄, R₅, R₆, R₇, R₈ andR₉ are independently alkyl, aryl, aryl-alkyl-, heterocycloalkyl, orheteroaryl each of which is further optionally substituted by one tofive substituents selected from the group consisting of (C₁-C₇) alkyl,halo, hydroxy, (C₁-C₇) alkoxy, and aryl; and X is selected fromhydrogen, amine, cyano, halogen, nitro, alkyl-S—, alkyl-SO—, alkyl-SO₂—,H₂N—SO₂—, R₅—C(O)—, alkyl, and R₄—O, wherein R₄ and R₅ are definedabove; or a pharmaceutically acceptable salt thereof, or an opticalisomer thereof; or a mixture of optical isomers.
 2. The compound ofclaim 1, wherein R₁ is selected from (C₆-C₁₂) aryl, (5-14) memberedheteroaryl, and (4-14) membered heterocycloalkyl, each of which isoptionally substituted by one to three substituents selected from thegroup consisting of HC(O)—, (5-9) membered heteroaryl, and (4-9)membered heterocycloalkyl, (C₁-C₇) alkyl, (C₃-C₇) cycloakyl, R₄—O—,R₅—C(O)—, R₆—SO₂—, (R₇)NH—C(O)—, and (R₈)(R₉)N—, wherein R₄, R₅, R₆, R₇,R₈ and R₉ are independently (C₁-C₇) alkyl or (C₆-C₁₂) aryl, each ofwhich is further optionally substituted by one to two substituentsselected from the group consisting of (C₁-C₇) alkyl, halo, hydroxy,(C₁-C₇) alkoxy, (C₆-C₁₂) aryl, (C₁-C₇) dialkylamino, and (4-9) memberedheterocycloalkyl; R₂ and R₃ are independently hydrogen, or (C₁-C₇)alkyl; X is selected from hydrogen, amine, cyano, halogen, nitro,alkyl-S—, alkyl-SO—, alkyl-SO₂—, H₂N—SO₂—, R₄—C(O)—, alkyl, and R₅-0,wherein R₄ and R₅ are defined above; or a pharmaceutically acceptablesalt thereof, or an optical isomer thereof; or a mixture of opticalisomers.
 3. A compound of formula (II)

wherein R′₁ is selected from hydrogen, alkyl, alkoxy, cycloakyl, R₄—O—,R₅C(O)—, R₆SO₂—, (R₇)NH—C(O)—, and (R₈)(R₉)N—, aryl, heteroaryl,heterocycloalkyl, said aryl, heteroaryl, and heterocycloalkyl areoptionally substituted by one or two substituents selected from hydroxy,halo, alkyl, carboxyl, alkoxycarbonyl, and HC(O)—; wherein R₄, R₅, R₆,R₇, R₈ and R₉ are independently alkyl or aryl each of which isoptionally substituted by one to five substituents selected from thegroup consisting of (C₁-C₇) alkyl, halo, hydroxyl, (C₁-C₇) alkoxy, andaryl; R₂ and R₃ are independently hydrogen, or (C₁-C₇) alkyl; X isselected from hydrogen, cyano, halogen, nitro, alkyl-S—, alkyl-SO—,alkyl-SO₂—, H₂N—SO₂—, R₅—C(O)—, alkyl, and R₄—O, wherein R₄ and R₅ areindependently alkyl or aryl each of which is optionally substituted bysubstituents selected from the group consisting of (C₁-C₇) alkyl, halo,hydroxyl, (C₁-C₇) alkoxy, and aryl; or a pharmaceutically acceptablesalt thereof, or an optical isomer thereof; or a mixture of opticalisomers.
 4. The compound of claim 3, wherein R′₁ is selected from(C₁-C₇) alkyl, (C₃-C₇) cycloalkyl, (C₁-C₇) alkoxy, HC(O)—, (5-9)membered heteroaryl, and (4-9) membered heterocycloalkyl, or (C₆-C₁₂)aryl, said (C₆-C₁₂) aryl, (5-9) membered heteroaryl, and (4-9) memberedheterocycloalkyl are optionally substituted by one or two substituentsselected from hydroxy, halo, (C₁-C₇) alkyl, carboxyl, (C₁-C₇)alkoxycarbonyl, and HC(O)—; R₂ and R₃ are hydrogen; X is halogen, or(C₁-C₇) alkoxy; or a pharmaceutically acceptable salt thereof, or anoptical isomer thereof; or a mixture of optical isomers.
 5. A compoundof formula (III)

wherein R′₁ is selected from hydrogen, alkyl, cycloakyl, R₅C(O)—,R₆SO₂—, (R₇)NH—C(O)—, and (R₈)(R₉)N—, aryl, heteroaryl,heterocycloalkyl, said aryl, heteroaryl, and heterocycloalkyl areoptionally substituted by one or two substituents selected fromalkyl-SO₂—, alkyl-C(O)—, heterocycloalkyl-alkyl-, alkyl-alkoxy-,alkoxy-, alkyl, aryl, cycloalkyl, halo, alkoxy-alkyl-, alkyl-O—C(O)—,cycloalkyl-alkyl-, dialkylamino-alkoxy-, and dialkylamino-alkyl-;wherein R₅, R₆, R₇, R₈ and R₉ are independently alkyl or aryl, each ofwhich is optionally substituted by one to five substituents selectedfrom the group consisting of (C₁-C₇) alkyl, halo, hydroxy, (C₁-C₇)alkoxy, and aryl; R₂ and R₃ are hydrogen; X is selected from hydrogen,cyano, halogen, nitro, alkyl-S—, alkyl-SO—, alkyl-SO₂—, H₂N—SO₂—,R₅—C(O)—, alkyl, and R₄—O, wherein R₄ and R₅ are independently alkyl oraryl each of which is optionally substituted by substituents selectedfrom the group consisting of (C₁-C₇) alkyl, halo, hydroxy, (C₁-C₇)alkoxy, and aryl; Y is C or N; or a pharmaceutically acceptable saltthereof, or an optical isomer thereof; or a mixture of optical isomers.6. The compound of claim 5, wherein R′₁ is selected from hydrogen,(C₁-C₄) alkyl, (C₆-C₁₂) aryl, (5-9) membered heteroaryl, (C₃-C₇)cycloalkyl-(C₁-C₄) alkyl-, each of which is optionally substituted byone or two substituents selected from the group consisting of (C₁-C₄)alkyl-SO₂—, (C₁-C₄) alkyl-C(O)—, (5-9) membered-heterocycloalkyl-(C₁-C₄)alkyl-, (C₁-C₄) alkyl-(C₁-C₄) alkoxy-, (C₁-C₄) alkoxy-, (C₁-C₄) alkyl,(C₃-C₇) cycloalkyl, halogen, (C₁-C₄) alkoxy-(C₁-C₄) alkyl-, (C₁-C₄)alkyl-O—C(O)—, (C₁-C₄) dialkylamino-(C₁-C₄) alkoxy-, and (C₁-C₄)dialkylamino-(C₁-C₄) alkyl-; R₂ and R₃ are hydrogen; X is hydrogen,halogen, or (C₁-C₇) alkyl; or a pharmaceutically acceptable saltthereof, or an optical isomer thereof; or a mixture of optical isomers.7. The compound of claim 5, wherein R′₁ is hydrogen, (C₁-C₄) alkyl,phenyl, pyridine, said pyridine is optionally substituted by one or twosubstituents selected from (C₃-C₇) cycloalkyl, (C₁-C₄) alkyl, halo,(C₁-C₄) alkoxy-(C₁-C₄) alkyl-, (5-9) membered-heterocycloalkyl-(C₁-C₄)alkyl-, (5-9) membered-heterocycloalkyl-(C₁-C₄) alkoxy-, and (C₁-C₄)dialkylamino-(C₁-C₄) alkyl-; R₂ and R₃ are hydrogen; X is halogen; Y isC or N; or a pharmaceutically acceptable salt thereof, or an opticalisomer thereof; or a mixture of optical isomers.
 8. A method ofinhibiting activity of MMP-2, and/or MMP-8, and/or MMP-9, and/or MMP-12and/or MMP-13 in a subject, comprising: administering to the subject atherapeutically effective amount of the compound according to claim 1 or3 or
 5. 9. A method of treating a disorder or a disease in a subjectmediated by MMP-2, and/or MMP-8, and/or MMP-9, and/or MMP-12 and/orMMP-13, comprising: administering to the subject a therapeuticallyeffective amount of the compound according to claim 1 or 3 or
 5. 10. Themethod of claim 9, wherein the disorder or the disease is selected fromthe group consisting of Alport syndrome, asthma, rhinitis, chronicobstructive pulmonary diseases (COPD), arthritis, atherosclerosis andrestenosis, cancer invasion and metastasis, diseases involving tissuedestruction, loosening of hip joint replacements, periodontal disease,fibrotic disease, infarction and heart disease, liver and renalfibrosis, endometriosis, diseases related to the weakening of theextracellular matrix, heart failure, aortic aneurysms, CNS relateddiseases, Alzheimer's disease and Multiple Sclerosis (MS), hematologicaldisorders.
 11. A pharmaceutical composition, comprising: atherapeutically effective amount of the compound of claim 1 or 3 or 5and one or more pharmaceutically acceptable carriers.
 12. Apharmaceutical composition, comprising: a therapeutically effectiveamount of the compound according to claim 1 or 3 or 5 and one or moretherapeutically active agents selected from 1) AT₁ receptor antagonistsselected from the group consisting of abitesartan, benzyllosartan,candesartan, elisartan, embusartan, enoltasosartan, eprosartan,fonsartan, forasartan, glycyllosartan, irbesartan, isoteoline, losartan,milfasartan, olmesartan, opomisartan, pratosartan, ripisartan,saprisartan, saralasin, sarmesin, tasosartan, telmisartan, valsartan,zolasartan; Kissei KRH-94, Lusofarmaco LR-B/057, Lusofarmaco LR-B/081,Lusofarmaco LR B/087, Searle SC-52458, Sankyo CS-866, Takeda TAK-536,Uriach UR-7247, A-81282, A-81988, BIBR-363, BIBS39, BIBS-222,BMS-180560, BMS-184698, CGP-38560A, CGP-48369, CGP-49870, CGP-63170,CI-996, CV-11194, DA-2079, DE-3489, DMP-811, DuP-167, DuP-532, GA-0056,E-4177, EMD-66397, EMD-73495, EXP-063, EXP-929, EXP-3174, EXP-6155,EXP-6803, EXP-7711, EXP-9270, FK-739, HN-65021, HR-720, ICI-D6888,ICI-D7155, ICI-D8731, KR1-1177, KT3-671, KW-3433, L-158809, L-158978,L-159282, L-159689, L-159874, L-161177, L-162154, L-162234, L-162441,L-163007, L-163017, LY-235656, LY-285434, LY-301875, LY-302289,LY-315995, ME-3221, PD-123177, PD-123319, PD-150304, RG-13647,RWJ-38970, RWJ-46458, S-8307, S-8308, SL-91.0102, U-96849, U-97018,UP-269-6, UP-275-22, WAY-126227, WK-1492.2K, WK-1360, X-6803, XH-148,XR-510, YM-358, YM-31472, ZD-6888, ZD-7155 and ZD-8731 which are allknown per se, or any physiologically compatible salts, solvates,prodrugs or esters thereof; 2) non-selective alpha-adrenoceptorantagonists, tolazoline or phenoxybenzamine; 3) selectivealpha-adrenoceptor antagonists, doxazosin, prazosin, terazosin orurapidil; beta-adrenoceptor antagonists, acebutolol, alprenolol,atenolol, betaxolol, bisoprolol, bupranolol, carazolol, carteolol,celiprolol, mepindolol, metipranolol, metoprolol, nadolol, oxprenolol,penbutolol, pindolol, propranolol, sotalol and timolol; 4) mixedantagonists of alpha- and beta-adrenoceptors, carvedilol or labetolol;ganglion blockers, reserpine or guanethidine; 5) alpha2-adrenoceptoragonists, centrally acting alpha2-adrenoceptor agonists, clonidine,guanfacine, guanabenz methyldopa and moxonidine; 6) rennin inhibitors,alskiren; 7) ACE inhibitors, benazepril, captopril, cilazapril,enalapril, fosinopril, imidapril, lisinopril, moexipril, quinapril,perindopril, ramipril, spirapril or trandolapril; 8) mixed or selectiveendothelin receptor antagonists atrasentan, bosentan, clazosentan,darusentan, sitaxsentan, tezosentan, BMS-193884 or J-104132; directvasodilators, diazoxide, dihydralazine, hydralazine or minoxidil; 9)mixed ACE/NEP dual inhibitors, omapatrilat; ECE inhibitors, FR-901533;PD-069185; CGS-26303; CGS-34043; CGS-35066; CGS-30084; CGS-35066;SM-19712; Ro0677447; 10) selective NEP inhibitors; 11) vasopressinantagonists; 12) aldosterone receptor antagonists, eplerenone; 13)aldosterone inhibitors; 14) angiotensin vaccine; 15) urotensin IIreceptor antagonists; and 16) an antiinflamatory agent and ananitrheumatic agent.
 13. A pharmaceutical composition, comprising: atherapeutically effective amount of the compound according to claim 1 or3 or 5 and one or more therapeutically active agents selected fromaromatase inhibitors; antiestrogens; topoisomerase I inhibitors;topoisomerase II inhibitors; microtubule active compounds; alkylatingcompounds; histone deacetylase inhibitors; compounds which induce celldifferentiation processes; cyclooxygenase inhibitors; MMP inhibitors;mTOR inhibitors; antineoplastic antimetabolites; platin compounds;compounds targeting/decreasing a protein or lipid kinase activity andfurther anti-angiogenic compounds; compounds which target, decrease orinhibit the activity of a protein or lipid phosphatase; gonadorelinagonists; anti-androgens; methionine aminopeptidase inhibitors;bisphosphonates; biological response modifiers; antiproliferativeantibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms;telomerase inhibitors; proteasome inhibitors; compounds used in thetreatment of hematologic malignancies; compounds which target, decreaseor inhibit the activity of Flt-3; Hsp90 inhibitors 17-AAG(17-allylaminogeldanamycin, NSC330507), 17-DMAG(17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545),IPI-504, CNF1010, CNF2024, CNF1010 from Conforma Therapeutics;temozolomide (TEMODAL®); kinesin spindle protein inhibitors, SB715992 orSB743921 from GlaxoSmithKline, or pentamidine/chlorpromazine fromCombinatoRx; MEK inhibitors ARRY142886 from Array PioPharma, AZD6244from AstraZeneca, PD181461 from Pfizer and leucovorin. 14-16. (canceled)